Substituted biaryl sulfonamides and the use thereof

ABSTRACT

Provided herein are substituted biaryl sulfonamide compounds, pharmaceutical compositions comprising the compounds, methods of their preparation, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or amelioration of various disorders, including cancer and proliferative disorders. In one embodiment, the compounds provided herein modulate initiation of protein translation. In one embodiment, the compounds provided herein are used in combination with surgery, radiation therapy, immuno therapy and/or one or more additional anticancer drugs for the treatment, prevention, and/or amelioration of cancer and proliferative disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 14/092,425, filed Nov. 27, 2013; which claims the benefit of U.S.Provisional Patent Application No. 61/732,218, filed Nov. 30, 2012; thedisclosure of each of which is incorporated herein by reference in itsentirety.

FIELD

Provided herein are substituted biaryl sulfonamide compounds,pharmaceutical compositions comprising the compounds, methods of theirpreparation, and methods of their use. The compounds provided herein areuseful for the treatment, prevention, and/or amelioration of variousdisorders, including cancer, proliferative disorders, and angiogenesismediated diseases.

BACKGROUND

Cancer is a major worldwide public health problem; in the United Statesalone, approximately 574,000 people died of cancer in 2010. See, e.g.,U.S. Mortality Data 2010, National Center for Health Statistics, Centersfor Disease Control and Prevention (2010). Many types of cancer havebeen described in the medical literature. Examples include cancer ofblood, bone, skin, lung, colon, breast, prostate, ovary, brain, kidney,bladder, pancreas, and liver, among others. The incidence of cancercontinues to climb as the general population ages and as new forms ofcancer develop. A continuing need exists for effective therapies totreat subjects with cancer. Breast cancer is one of the most commontypes of cancer, especially among women. In the United States, it isestimated that there will be about 230,000 new cases of breast cancerand about 40,000 deaths from breast cancer in 2012. See, e.g., BreastCancer Statistics, National Cancer Institute (2012), available atwww.cancer.gov. Among different types of breast cancer, triple negativebreast cancer (estrogen receptor (ER)/progesterone receptor/HER-2negative) is more aggressive than other breast cancer subtypes. Notargeted therapy exists for triple negative breast cancer. Triplenegative breast cancer has a higher rate of recurrence resulting indeath, although the tumors initially appear to respond to chemotherapy.Clearly there is a need to develop effective targeted therapy for triplenegative breast cancer.

Changes in protein synthesis are directly linked to multiple humancancers. Translation initiation is deregulated in many cancers,including, e.g., lymphoma, breast cancer, head and neck cancer,colorectal cancer, lung cancer, bladder cancer, cervical cancer, andprostate cancer. Many proteins supporting the high rate of cancer cellgrowth, proliferation, and survival are translated from mRNAs havingsecondary structures, which have a greater dependence on rate-limitingtranslation factors such as eukaryotic initiation factor 4E (eIF4E).eIF4E overexpression in tumors can be a predictor for relapse in breastcancer regardless of nodal status and for drug resistance to adjuvantchemotherapy. A high percentage (>60%) of triple negative breast tumorsexpress high levels of eIF4E. The patient group with high levels ofeIF4E has a 1.6-fold higher rate of recurrence and a 2.1-fold increasein relative risk for cancer death. High levels of eIF4E drive thetranslation of proteins responsible for cancer initiation andprogression resulting in aggressive phenotypes and enabling the tumorsto better survive radiation treatment and chemotherapy. Therefore, it isdesirable to regulate protein translation in cancer, in particular,inhibit the rate-limiting steps in protein translation in order tocontrol cell growth and proliferation.

eIF4E, the rate-limiting factor for eukaryotic protein translationinitiation, is ubiquitously expressed in multiple breast cancer celllines. The activity and availability of eIF4E are controlled, e.g., bybinding proteins such as 4E-BP1. The activity of these binding proteinsis in turn regulated by phosphorylation, particularly by mTOR. eIF4Eover-expression along with the concomitant enhanced translationinitiation drives cellular transformation and tumorigenesis. eIF4E is aconvergence point for many oncogenic pathways and a key factor formalignancy in human cancer tissues and in experimental cancer models.Enhanced translation initiation is found in malignant breast phenotypes.eIF4E over-expression leads to breast carcinoma angiogenesis andprogression. eIF4E elevation of 7-fold or more is a strong independentprognostic indicator for breast cancer relapse and death inretrospective and prospective studies. Antisense oligonucleotide therapydown-regulating eIF4E resulted in a reduction of in vivo tumor growth inPC-3 prostate and MDA-MB-231 breast cancer models in mice. No toxicitywas observed when 80% knockdown was observed in essential organs,suggesting tumors are more sensitive to translation initiationinhibition than normal tissue.

Translation initiation factor eIF4E and its binding protein 4E-BP1 aremajor downstream effectors of the PI3K/Akt/mTOR pathway. mTOR and othermembers of the PI3K/Akt/mTOR family control the establishment andmaintenance of cancer phenotypes. The PI3K/Akt/mTOR pathway has beenclinically validated as a target for cancer therapies. Overactivation ofPI3K and Akt is found in a wide range of tumor types. PI3K catalyzes theproduction of phosphatidylinositol-3,4,5-trisphosphate. This lipidactivates Akt protein kinase, which in turn triggers a cascade ofresponses ranging from cell growth and proliferation to survival andmotility. PTEN, a dual specificity phosphatase, is an inhibitor of thePI3K pathway. Second to p53, PTEN is most frequently mutated or deletedin human tumors. Several PI3K inhibitors have been developed in clinicaltrials. mTOR controls translation initiation through phosphorylation andinactivation of 4E-BP binding protein, thereby activating eIF4E.Activation of eIF4E is required for the translation initiation of mRNAsthat have long structured ‘5-untranslated regions. Increasing evidencesuggests that mTOR, as a central regulator of cell growth andproliferation, controls protein biosynthesis. The mTOR pathway controlstranslation of mRNAs encoding proteins such as cyclin Dl, c-Myc, andornithine decarboxylase that are essential for G1 cell-cycle progressionand S-phase initiation. Inhibition of mTOR results in G1 cell cyclearrest. Rapamycin, an mTOR inhibitor, has significant antitumor activityagainst many tumor cell lines in the NCI screening as well as in humans.However, formulation, solubility and stability issues have hindered thedevelopment of rapamycin. Analogs of rapamycin have been developed toaddress these issues and have shown promising results in Phase II/IIIclinical trials. There remains a need for alternative cancer therapeuticagents that are effective and safe, e.g., agents having maximuminhibition of tumor growth, minimal toxicity to normal cells, andminimal on-target side effects in the treated subjects.

Excessive and persistent activation of cells characterizes both cancerand fibrotic diseases. Fibrosis is the formation of excess fibrousconnective tissue in an organ or tissue in a reparative or reactiveprocess, which can be benign (e.g., wound healing) or pathological. Theterm fibrosis is often used to indicate a pathological state of excessdeposition of connective tissue, which can lead to loss of function andorgan failure. During wound healing myofibroblasts are specialized cellsthat acquire smooth muscle features (including α-smooth muscle actin)and are important contributors to tissue repair. Myofibroblasts can bederived from fibroblasts, epithelial cells, and endothelial cells andare characterized by their ability to secrete extracellular matrix.Regardless of their origin, TGF-β is the principle growth factorresponsible for differentiation to the myofibroblast activated phenotype(J L Barnes, Y Gorin, Myofibroblast Differentiation During Fibrosis:Role of NAD(P)H Oxidases, Kidney Int. 2011, 79: 944-956). During normaltissue repair myofibroblasts are activated in a controlled and transientmanner (Hinz B. et al., Recent developments in myofibroblast biology:paradigms for connective tissue remodeling, Am J Pathol. 2012,180:1340-55). However, excessive and persistent activation ofmyofibroblasts plays a key role in both fibrotic disease and cancer. Infibrotic disease, large numbers of myofibroblasts accumulate and areresponsible for the uncontrolled production of extracellular matrixwhich leads to loss of function and organ failure. Fibrotic diseasesinclude a variety of clinical entities, including organ specificfibrosis (heart, liver, lung, kidney, bone marrow, skin, pancreas),other forms of fibrosis (retroperitoneal, nephrogenic, and cystic), andconnective tissue disorders (atherosclerosis, cirrhosis, scleroderma,keloids, Crohn's disease, and endometriosis). In cancer, the tumorstroma microenvironment contains large numbers of myofibroblasts as wellas other cells, which are collectively referred to as cancer associatedfibroblasts. Cancer associated fibroblasts play a major role in tumorinitiation, progression, and metastais through the production of avariety of growth factors, ECM proteins, and other pro-angiogenic andpro-metastatic factors (Khamis Z I, et al., Active roles of tumor stromain breast cancer metastasis, Int J Breast Cancer, 2012, 2012:574025).

Therefore, drugs which inhibit the transition of fibroblasts tomyofibroblasts have potential for the treatment of cancer, theprevention and treatment of metastatsis, and the treatment of a varietyof fibrotic diseases.

SUMMARY

Provided herein are compounds of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein R, R′, X, and Y are defined herein elsewhere. The compounds areuseful for the treatment, prevention, and/or amelioration of variousdisorders, such as cancer and proliferative disorders.

Also provided herein are pharmaceutical compositions and dosage formscomprising a compound provided herein, e.g., a compound of formula (I),or an enantiomer, a mixture of enantiomers or a mixture of diastereomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof. In one embodiment, the pharmaceutical compositions anddosage forms further comprise one or more pharmaceutically acceptablecarriers or excipients. In one embodiment, the compositions and dosageforms provided herein further comprise one or more additional activeagents, such as, e.g., a cancer therapeutic agent.

Also provided herein are methods for the treatment, prevention, and/oramelioration of one or more symptoms of a disorder, such as cancer or aproliferative disorder, in a subject, comprising administering to thesubject a therapeutically effective amount of a compound providedherein, e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof. In one embodiment,the subject is a human. Also provided herein are uses of compounds orcompositions provided herein in the manufacture of a medicament for thetreatment, prevention, and/or amelioration of various disorders providedherein. Also provided herein are compounds and compositions for use inthe treatment, prevention, and/or amelioration of various disordersprovided herein. Disorders that may be treated, prevented, and/orameliorated include, but are not limited to, cancer, proliferativedisorders, breast cancer (e.g., triple negative breast cancer, ER+breast cancer, or ER− breast cancer), basal cell nevus syndrome (Gorlinsyndrome), basal cell carcinoma, skin cancer, lung cancer, small celllung cancer, non-small cell lung cancer, brain cancer, medulloblastoma,glioblastoma, colorectal cancer, ovarian cancer, liver cancer,pancreatic cancer (e.g., carcinoma, angiosarcoma, adenosarcoma), gastriccancer, gastroesophageal junction cancer, prostate cancer, cervicalcancer, bladder cancer, head and neck cancer, lymphoma (e.g., mantlecell lymphoma, diffuse large B-cell lymphoma), solid tumors that cannotbe removed by surgery, locally advanced solid tumors, metastatic solidtumors, leukemia (e.g., acute myeloid leukemia (AML), acutelymphoblastic leukemia (ALL), or chronic myeloid leukemia (CML)), orrecurrent or refractory tumors.

In one embodiment, provided herein is a method of inhibiting or reducingthe activity of eIF4E. In one embodiment, the method comprisesdisrupting the eIF4F complex with a compound provided herein, e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof. In one embodiment, the methodcomprises downregulating protein translation initiation with a compoundprovided herein, e.g., a compound of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the effect of Compound 1 and Compound 2 on inhibitingα-smooth muscle actin in vitro activity in normal human lung fibroblasts(NHLFs).

FIG. 2 illustrates the effect of Compound 2, and Compounds 5 to 10 oninhibiting α-smooth muscle actin in vitro activity in normal human lungfibroblasts (NHLFs).

FIG. 3 illustrates the effect (e.g., mean tumor volume) of Compound 1 oninhibiting in vivo tumor growth in the MDA-MB-231 xenograft model forbreast cancer in nude mice.

FIG. 4 illustrates the effect (e.g., percent weight change) of Compound1 on inhibiting in vivo tumor growth in the MDA-MB-231 xenograft modelfor breast cancer in nude mice.

FIG. 5 illustrates the effect of Compound 1 on inhibiting in vivo tumorgrowth in the MDA-MB-231 xenograft model for breast cancer in nude miceduring the drug withdrawl phase.

FIG. 6 illustrates the effect (e.g., mean tumor size) of Compound 1 and2 on inhibiting in vivo tumor growth in the MDA-MB-231 xenograft modelfor breast cancer in nude mice.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art. All publications and patents referred to herein areincorporated by reference herein in their entireties.

A. DEFINITIONS

As used in the specification and the accompanying claims, the indefinitearticles “a” and “an” and the definite article “the” include plural aswell as singular referents, unless the context clearly dictatesotherwise.

As used herein, and unless otherwise indicated, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, or 0.05% of a given value or range.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a linear or branched saturated monovalent hydrocarbon radical,wherein the alkyl may optionally be substituted with one or moresubstituents. The term “alkyl” also encompasses both linear and branchedalkyl, unless otherwise specified. In certain embodiments, the alkyl isa linear saturated monovalent hydrocarbon radical that has 1 to 20(C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 12 (C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6(C₁₋₆) carbon atoms, or branched saturated monovalent hydrocarbonradical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ alkyl groups are also referred as “lower alkyl.” Examplesof alkyl groups include, but are not limited to, methyl, ethyl, propyl(including all isomeric forms), n-propyl, isopropyl, butyl (includingall isomeric forms), n-butyl, isobutyl, t-butyl, pentyl (including allisomeric forms), and hexyl (including all isomeric forms). For example,C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbon radicalof 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbonradical of 3 to 6 carbon atoms. In one embodiment, the alkyl has 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms. In one embodiment, the alkyl has 3 to 20 (C₃₋₂₀), 3to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. In one embodiment, the alkyl has 2 to 6 (C₂₋₆), 2 to 5 (C₂₋₅), 2to 4 (C₂₋₄), 2 to 3 (C₂₋₃), 3 to 6 (C₃₋₆), 3 to 5 (C₃₋₅), 3 to 4 (C₃₋₄),4 to 6 (C₄₋₆), 4 to 5 (C₄₋₅), or 5 to 6 (C₅₋₆) carbon atoms.

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted one or moresubstituents. The term “alkenyl” also encompasses radicals having “cis”and “trans” configurations, or alternatively, “E” and “Z”configurations, as appreciated by those of ordinary skill in the art. Asused herein, the term “alkenyl” encompasses both linear and branchedalkenyl, unless otherwise specified. For example, C₂₋₆ alkenyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkenyl groups include, but are not limited to, ethenyl, propen-1-yl,propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted one or moresubstituents. The term “alkynyl” also encompasses both linear andbranched alkynyl, unless otherwise specified. In certain embodiments,the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radical of 3to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groups include, but arenot limited to, ethynyl (—C≡CH) and propargyl (—CH₂C≡CH). For example,C₂₋₆ alkynyl refers to a linear unsaturated monovalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated monovalenthydrocarbon radical of 3 to 6 carbon atoms.

As used herein, and unless otherwise specified, the term “cycloalkyl”refers to a cyclic saturated bridged and/or non-bridged monovalenthydrocarbon radical, which may be optionally substituted one or moresubstituents as described herein. In certain embodiments, the cycloalkylhas from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12 (C₃₋₁₂),from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, andadamantyl.

As used herein, and unless otherwise specified, the term “heteroalkyl”refers to a stable straight or branched chain, or cyclic hydrocarbonradical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsare optionally oxidized and the nitrogen heteroatom can optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group. The heteroatom Si can be placed atany position of the heteroalkyl group, including the position at whichthe alkyl group is attached to the remainder of the molecule. Theheteroatom O, N, or S cannot be placed at the position at which thealkyl group is attached to the remainder of the molecule. The heteroatomO, N, or S can be placed at the external position distal to where thealkyl group is attached to the remainder of the molecule. Examplesinclude —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomscan be consecutive, such as, for example, —CH2-NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Also included in the term “heteroalkyl” are thoseradicals described as “heteroalkylene” and “heterocycloalkyl.” The term“heteroalkylene” by itself or as part of another substituent means adivalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Still further, forheteroalkylene linking groups, as well as all other linking groupprovided herein, no orientation of the linking group is implied.

As used herein, and unless otherwise specified, the term “aryl” refersto a monocyclic aromatic group and/or multicyclic monovalent aromaticgroup that contain at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), orfrom 6 to 10 (C₆₋₁₀) ring atoms. Examples of aryl groups include, butare not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl,phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers tobicyclic or tricyclic carbon rings, where one of the rings is aromaticand the others of which may be saturated, partially unsaturated, oraromatic, for example, dihydronaphthyl, indenyl, indanyl, ortetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may alsobe optionally substituted with one or more substituents.

As used herein, and unless otherwise specified, the term “arylalkyl” or“aralkyl” refers to a monovalent alkyl group substituted with aryl. Incertain embodiments, both alkyl and aryl may be optionally substitutedwith one or more substituents.

As used herein, and unless otherwise specified, the term “heteroaryl”refers to a monocyclic aromatic group and/or multicyclic aromatic groupthat contain at least one aromatic ring, wherein at least one ringcontains one or more heteroatoms independently selected from O, S, andN. Each ring of a heteroaryl group can contain one or two O atoms, oneor two S atoms, and/or one to four N atoms, provided that the totalnumber of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, andtriazolyl. Examples of bicyclic heteroaryl groups include, but are notlimited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl,benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl,imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl,isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl,pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclicheteroaryl groups include, but are not limited to, acridinyl,benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl,phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may beoptionally substituted with one or more substituents.

As used herein, and unless otherwise specified, the term “heterocyclyl,”“heterocycloalkyl,” or “heterocyclic” refers to a monocyclicnon-aromatic ring system and/or multicyclic ring system that contains atleast one non-aromatic ring, wherein at least one ring contains one ormore heteroatoms independently selected from O, S, or N; and theremaining ring atoms are carbon atoms. In certain embodiments, theheterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certainembodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which may include a fused or bridged ringsystem, and in which the nitrogen or sulfur atoms may be optionallyoxidized, the nitrogen atoms may be optionally quaternized, and somerings may be partially or fully saturated, or aromatic. The heterocyclylmay be attached to the main structure at any heteroatom or carbon atomwhich results in the creation of a stable compound. Examples of suchheterocyclic radicals include, but are not limited to, azepinyl,benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may beoptionally substituted with one or more substituents.

As used herein, and unless otherwise specified, the term “halogen”,“halide” or “halo” refers to fluorine, chlorine, bromine, and/or iodine.

As used herein, and unless otherwise specified, the term “hydrogen”encompasses proton (¹H), deuterium (²H), tritium (³H), and/or mixturesthereof.

As used herein, and unless otherwise specified, the term “optionallysubstituted” is intended to mean that a group, such as an alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl, orheterocyclyl, may be substituted with one or more substituentsindependently selected from, e.g., (a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹; and (b) halo,cyano (—CN), nitro (—NO₂), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heteroaryl or heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹.

In one embodiment, each Q¹ is independently selected from the groupconsisting of (a) cyano, halo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids such as, but not limited to, acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic,glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, propionic, phosphoric, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Insome embodiments, the salt is formed from hydrochloric, hydrobromic,phosphoric, or sulfuric acid. In one embodiment, the salt is formed fromhydrochloride salt.

As used herein, and unless otherwise specified, the term “hydrate” meansa compound provided herein or a salt thereof, which further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound provided herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate (e.g., mono-hydrate, dihydrate, trihydrate,tetrahydrate and the like).

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

In certain embodiments, as used herein, and unless otherwise specified,“optically active” and “enantiomerically active” refer to a collectionof molecules, which has an enantiomeric excess of no less than about50%, no less than about 70%, no less than about 80%, no less than about90%, no less than about 91%, no less than about 92%, no less than about93%, no less than about 94%, no less than about 95%, no less than about96%, no less than about 97%, no less than about 98%, no less than about99%, no less than about 99.5%, or no less than about 99.8%. In certainembodiments, the compound comprises about 95% or more of the desiredenantiomer and about 5% or less of the less preferred enantiomer basedon the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) or (−), is not related to the absolute configuration of themolecule, R or S.

As used herein, and unless otherwise specified, the terms “composition,”“formulation,” and “dosage form” are intended to encompass productscomprising the specified ingredient(s) (in the specified amounts, ifindicated), as well as any product(s) which result, directly orindirectly, from combination of the specified ingredient(s) in thespecified amount(s).

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologicallyacceptable excipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,excipient, solvent, or encapsulating material. In one embodiment, eachcomponent is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients of a pharmaceutical formulation,and suitable for use in contact with the tissue or organ of humans andanimals without excessive toxicity, irritation, allergic response,immunogenicity, or other problems or complications, commensurate with areasonable benefit/risk ratio. In one embodiment, by “pharmaceutical” or“pharmaceutically acceptable” it is meant that any diluent(s),excipient(s) or carrier(s) in the composition, formulation, or dosageform are compatible with the other ingredient(s) and not deleterious tothe recipient thereof. See, e.g., Remington: The Science and Practice ofPharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia,Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation: 2005; and Handbook of Pharmaceutical Additives, 3rdEdition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed.,CRC Press LLC: Boca Raton, Fla., 2009.

As used herein, and unless otherwise specified, the terms “activeingredient” and “active substance” refer to a compound, which isadministered, alone or in combination with one or more pharmaceuticallyacceptable excipients, to a subject for treating, preventing, managing,or ameliorating one or more symptoms of a condition, disorder, ordisease. As used herein, “active ingredient” and “active substance” maybe an optically active isomer of a compound described herein.

As used herein, and unless otherwise specified, the terms “drug,”“therapeutic agent,” and “chemotherapeutic agent” refer to a compound,or a pharmaceutical composition thereof, which is administered to asubject for treating, preventing, managing, or ameliorating one or moresymptoms of a condition, disorder, or disease.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compound ordosage form provided herein, with or without one or more additionalactive agent(s), after the diagnosis or onset of symptoms of theparticular disease.

As used herein, and unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound or dosage form providedherein, with or without one or more other additional active agent(s),prior to the onset of symptoms, particularly to patients at risk ofdisease or disorders provided herein. The terms encompass the inhibitionor reduction of a symptom of the particular disease. In certainembodiments, subjects with familial history of a disease are potentialcandidates for preventive regimens. In certain embodiments, subjects whohave a history of recurring symptoms are also potential candidates forthe prevention. In this regard, the term “prevention” may beinterchangeably used with the term “prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, “amelioration” of thesymptoms of a particular disorder by administration of a particularpharmaceutical composition refers to any lessening, whether permanent ortemporary, lasting or transient, that can be attributed to or associatedwith the administration of the composition.

As used herein, and unless otherwise specified, the term“therapeutically effective amount” or “effective amount” of a compoundmeans an amount sufficient to provide a therapeutic benefit in thetreatment or management of a disease or disorder, or to delay orminimize one or more symptoms associated with the disease or disorder. A“therapeutically effective amount” or “effective amount” of a compoundmeans an amount of therapeutic agent, alone or in combination with oneor more other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” and “effective amount” can encompassan amount that improves overall therapy, reduces, delays, or avoidssymptoms or causes of disease or disorder, or enhances the therapeuticefficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with one or more other therapies, which providesa prophylactic benefit in the prevention of the disease. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In specific embodiments, thesubject is a human. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

As used herein, and unless otherwise specified, “tumor” refers to allneoplastic cell growth and proliferation, whether malignant or benign,and all pre-cancerous and cancerous cells and tissues. As used herein,and unless otherwise specified, “neoplastic” refers to any form ofdysregulated or unregulated cell growth, whether malignant or benign,resulting in abnormal tissue growth. Thus, “neoplastic cells” includemalignant and benign cells having dysregulated or unregulated cellgrowth.

As used herein, and unless otherwise specified, the terms “cancer” and“cancerous” refer to or describe the physiological condition in mammalsthat is typically characterized by unregulated cell growth. Examples ofcancer include, but are not limited to, lymphoma, leukemia, and solidtumors, such as, for example, lung cancer.

As used herein, and unless otherwise specified, the term “proliferative”disorder or disease refers to unwanted cell proliferation of one or moresubset of cells in a multicellular organism resulting in harm (i.e.,discomfort or decreased life expectancy) to the multicellular organism.For example, as used herein, proliferative disorder or disease includesneoplastic disorders and other proliferative disorders.

As used herein, and unless otherwise specified, the term “triplenegative breast cancer” refers to specific subtypes of breast cancerthat are negative clinically for the expression of estrogen receptor(ER), progesterone receptor (PR) and human epidermal growth factorreceptor 2 (HER2) protein. These subtypes of breast cancer are generallydiagnosed based upon the presence or the lack of three receptors knownto fuel most breast cancers: estrogen receptors, progesterone receptorsand human epidermal growth factor receptor 2. None of these receptorsare found in patients diagnosed with triple negative breast cancer. Inother words, a triple negative breast cancer diagnosis means that theoffending tumor is estrogen receptor-negative, progesteronereceptor-negative and HER2-negative.

As used herein, and unless otherwise specified, the term “relapsed”refers to a situation where a subject, that has had a remission ofcancer after a therapy, has a return of cancer cells.

As used herein, and unless otherwise specified, the term “refractory” or“resistant” refers to a circumstance where a subject, even afterintensive treatment, has residual cancer cells in the body.

As used herein, and unless otherwise specified, the term “drugresistance” refers to the condition when a disease does not respond tothe treatment of a drug or drugs. Drug resistance can be eitherintrinsic, which means the disease has never been responsive to the drugor drugs, or it can be acquired, which means the disease ceasesresponding to a drug or drugs that the disease had previously respondedto. In certain embodiments, drug resistance is intrinsic. In certainembodiments, the drug resistance is acquired.

As used herein, and unless otherwise specified, the term “anticanceragent” or “cancer therapeutic agent” is meant to includeanti-proliferative agents and chemotherapeutic agents, including, butnot limited to, antimetabolites (e.g., 5-fluoro uracil, methotrexate,fludarabine, cytarabine (also known as cytosine arabinoside or Ara-C),and high dose cytarabine), antimicrotubule agents (e.g., vincaalkaloids, such as vincristine and vinblastine; and taxanes, such aspaclitaxel and docetaxel), alkylating agents (e.g., mechlorethamine,chlorambucil, cyclophosphamide, melphalan, melphalan, ifosfamide,carmustine, azacitidine, decitabine, busulfan, cyclophosphamide,dacarbazine, ifosfamide, and nitrosoureas, such as carmustine,lomustine, bischloroethylnitrosurea, and hydroxyurea), platinum agents(e.g., cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), andCI-973), anthracyclines (e.g., doxorubicin and daunorubicin), antitumorantibiotics (e.g., mitomycin, bleomycin, idarubicin, adriamycin,daunomycin (also known as daunorubicin, rubidomycin, or cerubidine), andmitoxantrone), topoisomerase inhibitors (e.g., etoposide andcamptothecins), purine antagonists or pyrimidine antagonists (e.g.,6-mercaptopurine, 5-fluorouracil, cytarabine, clofarabine, andgemcitabine), cell maturing agents (e.g., arsenic trioxide andtretinoin), DNA repair enzyme inhibitors (e.g., podophyllotoxines,etoposide, irinotecan, topotecan, and teniposide), enzymes that preventcell survival (e.g., asparaginase and pegaspargase), histone deacetylaseinhibitors (e.g., vorinostat), any other cytotoxic agents (e.g.,estramustine phosphate, dexamethasone, prednimustine, and procarbazine),hormones (e.g., dexamethasone, prednisone, methylprednisolone,tamoxifen, leuprolide, flutamide, and megestrol), monoclonal antibodies(e.g., gemtuzumab ozogamicin, alemtuzumab, rituximab, andyttrium-90-ibritumomab tiuxetan), immuno-modulators (e.g., thalidomideand lenalidomide), Bcr-Abl kinase inhibitors (e.g., AP23464, AZD0530,CGP76030, PD180970, SKI-606, imatinib, BMS354825 (dasatinib), AMN107(nilotinib), and VX-680), hormone agonists or antagonists, partialagonists or partial antagonists, kinase inhibitors, surgery,radiotherapy (e.g., gamma-radiation, neutron bean radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes), endocrine therapy, biological response modifiers(e.g., interferons, interleukins, and tumor necrosis factor),hyperthermia and cryotherapy, and agents to attenuate any adverseeffects (e.g., antiemetics). In one embodiment, the anticancer agent orcancer therapeutic agent is a cytotoxic agent, an antimetabolite, anantifolate, an HDAC inhibitor such as MGCD0103 (a.k.a.N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide),a DNA intercalating agent, a DNA cross-linking agent, a DNA alkylatingagent, a DNA cleaving agent, a topoisomerase inhibitor, a CDK inhibitor,a JAK inhibitor, an anti-angiogenic agent, a Bcr-Abl inhibitor, an HER2inhibitor, an EGFR inhibitor, a VEGFR inhibitor, a PDGFR inhibitor, anHGFR inhibitor, an IGFR inhibitor, a c-Kit inhibitor, a Ras pathwayinhibitor, a PI3K inhibitor, a multi-targeted kinase inhibitor, an mTORinhibitor, an anti-estrogen, an anti-androgen, an aromatase inhibitor, asomatostatin analog, an ER modulator, an anti-tubulin agent, a vincaalkaloid, a taxane, an HSP inhibitor, a Smoothened antagonist, atelomerase inhibitor, a COX-2 inhibitor, an anti-metastatic agent, animmunosuppressant, a biologics such as antibodies and hormonaltherapies.

As used herein, and unless otherwise specified, the terms“co-administration” and “in combination with” include the administrationof two or more therapeutic agents simultaneously, concurrently orsequentially within no specific time limits unless otherwise indicated.In one embodiment, the agents are present in the cell or in thesubject's body at the same time or exert their biological or therapeuticeffect at the same time. In one embodiment, the therapeutic agents arein the same composition or unit dosage form. In other embodiments, thetherapeutic agents are in separate compositions or unit dosage forms. Incertain embodiments, a first agent can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),essentially concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapeutic agent.

B. COMPOUNDS

In one embodiment, provided herein is a compound of formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH;

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

n is 2, 3, or 4;

each occurrence of R is independently hydrogen, (C₁-C₆)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which isoptionally substituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a) and R_(b) together form a 3 to 10membered ring. In one embodiment of a compound of formula (I), X is NH,and Y is S(O)₂. In another embodiment of a compound of formula (I), X isS(O)₂, and Y is NH. In one embodiment of a compound of formula (I), R′is hydrogen, halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy,(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl,alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxyare each optionally substituted with one or more halogen. In oneembodiment of a compound of formula (I), R′ is hydrogen, halogen,(C₁-C₈)alkyl, or (C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (I), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or(C₁-C₄)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (I), R′ is hydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃. Inone embodiment of a compound of formula (I), R′ is hydrogen or(C₁-C₄)alkyl. In one embodiment of a compound of formula (I), R′ ishydrogen or methyl. In one embodiment of a compound of formula (I), R′is hydrogen. In another embodiment of a compound of formula (I), R′ ismethyl. In yet another embodiment of a compound of formula (I), R′ isCl. In one embodiment of a compound of formula (I), R′ is Br.

In one embodiment of a compound of formula (I), n is 2. In anotherembodiment of a compound of formula (I), n is 3. In yet anotherembodiment of a compound of formula (I), n is 4. In yet anotherembodiment of a compound of formula (I), n is 2 or 3. In yet anotherembodiment of a compound of formula (I), n is 3 or 4.

In one embodiment of a compound of formula (I), each occurrence of R isindependently hydrogen, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (I), eachoccurrence of R is independently (C₁-C₄)alkyl. In one embodiment of acompound of formula (I), each occurrence of R is independently methyl,ethyl, isopropyl, or tert-butyl. In one embodiment of a compound offormula (I), each occurrence of R is independently isopropyl.

In one embodiment, provided herein is a compound of formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein

X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH;

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

n is 2, 3, or 4;

each occurrence of R is independently, (C₂-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or Ra and Rb together form a 3 to 10 memberedring.

In one embodiment of a compound of formula (I), X is NH, and Y is S(O)2.In another embodiment of a compound of formula (I), X is S(O)2, and Y isNH.

In one embodiment of a compound of formula (I), R′ is hydrogen, halogen,cyano, (C1-C8)alkyl, (C2-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (I), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (I), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy,wherein the alkyl and alkoxyl are each optionally substituted with oneor more halogen. In one embodiment of a compound of formula (I), R′ ishydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃. In one embodiment of acompound of formula (I), R′ is hydrogen or (C₁-C₄)alkyl. In oneembodiment of a compound of formula (I), R′ is hydrogen or methyl. Inone embodiment of a compound of formula (I), R′ is hydrogen. In anotherembodiment of a compound of formula (I), R′ is methyl. In anotherembodiment of a compound of formula (I), R′ is Cl.

In one embodiment of a compound of formula (I), n is 2. In anotherembodiment of a compound of formula (I), n is 3. In yet anotherembodiment of a compound of formula (I), n is 4. In yet anotherembodiment of a compound of formula (I), n is 2 or 3. In yet anotherembodiment of a compound of formula (I), n is 3 or 4.

In one embodiment of a compound of formula (I), each occurrence of R isindependently, (C₂-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (I), eachoccurrence of R is independently (C₂-C₄)alkyl. In one embodiment of acompound of formula (I), each occurrence of R is independently ethyl, orisopropyl. In one embodiment of a compound of formula (I), eachoccurrence of R is independently isopropyl.

In one embodiment, provided herein is a compound of formula (II):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH;

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

R₁ is independently (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl, each of which is optionally substituted with one ormore halogen;

R₂ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R₃ is independently (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl, each of which is optionally substituted with one ormore halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a). and R_(b) together form a 3 to 10membered ring.

In one embodiment of a compound of formula (II), X is NH, and Y isS(O)₂. In another embodiment of a compound of formula (II), X is S(O)₂,and Y is NH.

In one embodiment of a compound of formula (II), R′ is hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (II), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (II), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy,wherein the alkyl and alkoxyl are each optionally substituted with oneor more halogen. In one embodiment of a compound of formula (II), R′ ishydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃. In one embodiment of acompound of formula (II), R′ is hydrogen or (C₁-C₄)alkyl. In oneembodiment of a compound of formula (II), R′ is hydrogen or methyl. Inone embodiment of a compound of formula (II), R′ is hydrogen. In anotherembodiment of a compound of formula (II), R′ is methyl. In anotherembodiment of a compound of formula (II), R′ is Cl. In one embodiment ofa compound of formula (I), R′ is Br.

In one embodiment of a compound of formula (II), R₁ is (C₁-C₄)alkyl. Inone embodiment of a compound of formula (II), R₁ is methyl, ethyl, orisopropyl. In one embodiment of a compound of formula (II), R₂ ishydrogen, or (C₁-C₄)alkyl. In one embodiment of a compound of formula(II), R₂ is methyl, isopropyl, or tert-butyl. In one embodiment of acompound of formula (II), R₃ is (C₁-C₄)alkyl. In one embodiment of acompound of formula (II), R₃ is methyl, ethyl or isopropyl.

In one embodiment, provided herein is a compound of formula (II):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH;

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

R₁, R₂, and R₃ are independently (C₂-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a) and R_(b) together form a 3 to 10membered ring.

In one embodiment of a compound of formula (II), X is NH, and Y isS(O)₂. In another embodiment of a compound of formula (II), X is S(O)₂,and Y is NH.

In one embodiment of a compound of formula (II), R′ is hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (II), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (II), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy,wherein the alkyl and alkoxyl are each optionally substituted with oneor more halogen. In one embodiment of a compound of formula (II), R′ ishydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃. In one embodiment of acompound of formula (II), R′ is hydrogen or (C₁-C₄)alkyl. In oneembodiment of a compound of formula (II), R′ is hydrogen or methyl. Inone embodiment of a compound of formula (II), R′ is hydrogen. In anotherembodiment of a compound of formula (II), R′ is methyl. In anotherembodiment of a compound of formula (II), R′ is Cl.

In one embodiment of a compound of formula (II), R₁, R₂, and R₃ areindependently (C₂-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (II), R₁is (C₂-C₄)alkyl. In one embodiment of a compound of formula (II), R₁ isisopropyl. In one embodiment of a compound of formula (II), R₂ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (II), R₂ isisopropyl. In one embodiment of a compound of formula (II), R₃ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (II), R₃ isisopropyl.

In one embodiment, provided herein is a compound of formula (III):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R′, R₁, R₂, and R₃ are each as defined herein.

In one embodiment of a compound of formula (III), R₁ is (C₁-C₄)alkyl. Inone embodiment of a compound of formula (III), R₁ is methyl, ethyl, orisopropyl. In one embodiment of a compound of formula (III), R₂ ishydrogen, or (C₁-C₄)alkyl. In one embodiment of a compound of formula(III), R₂ is methyl, isopropyl, or tert-butyl. In one embodiment of acompound of formula (III), R₃ is (C₁-C₄)alkyl. In one embodiment of acompound of formula (III), R₃ is methyl, ethyl or isopropyl.

In one embodiment, provided herein is a compound of formula (III):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

R₁, R₂, and R₃ are independently (C₂-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a). and R_(b) together form a 3 to 10membered ring.

In one embodiment of a compound of formula (III), R′ is hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (III), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (III), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy,wherein the alkyl and alkoxyl are each optionally substituted with oneor more halogen. In one embodiment of a compound of formula (III), R′ ishydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃. In one embodiment of acompound of formula (III), R′ is hydrogen or (C₁-C₄)alkyl. In oneembodiment of a compound of formula (III), R′ is hydrogen or methyl. Inone embodiment of a compound of formula (III), R′ is hydrogen. Inanother embodiment of a compound of formula (III), R′ is methyl. In yetanother embodiment of a compound of formula (III), R′ is Cl.

In one embodiment of a compound of formula (III), R₁, R₂, and R₃ areindependently (C₂-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (III), R₁is (C₂-C₄)alkyl. In one embodiment of a compound of formula (III), R₁ isisopropyl. In one embodiment of a compound of formula (III), R₂ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (III), R₂ isisopropyl. In one embodiment of a compound of formula (III), R₃ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (III), R₃ isisopropyl.

In one embodiment, provided herein is a compound of formula (IV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R′, R₁, R₂, and R₃ are each as defined herein.

In one embodiment of a compound of formula (IV), R₁ is (C₁-C₄)alkyl. Inone embodiment of a compound of formula (IV), R₁ is methyl, ethyl, orisopropyl. In one embodiment of a compound of formula (IV), R₂ ishydrogen, or (C₁-C₄)alkyl. In one embodiment of a compound of formula(IV), R₂ is methyl, isopropyl, or tert-butyl. In one embodiment of acompound of formula (IV), R₃ is (C₁-C₄)alkyl. In one embodiment of acompound of formula (IV), R₃ is methyl, ethyl or isopropyl.

In one embodiment, provided herein is a compound of formula (IV):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

R₁, R₂, and R₃ are independently (C₂-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a). and R_(b) together form a 3 to 10membered ring.

In one embodiment of a compound of formula (IV), R′ is hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (IV), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (IV), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy,wherein the alkyl and alkoxyl are each optionally substituted with oneor more halogen. In one embodiment of a compound of formula (IV), R′ ishydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃. In one embodiment of acompound of formula (IV), R′ is hydrogen or (C₁-C₄)alkyl. In oneembodiment of a compound of formula (IV), R′ is hydrogen or methyl. Inone embodiment of a compound of formula (IV), R′ is hydrogen. In anotherembodiment of a compound of formula (IV), R′ is methyl. In yet anotherembodiment of a compound of formula (IV), R′ is Cl.

In one embodiment of a compound of formula (IV), R₁, R₂, and R₃ areindependently (C₂-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (IV), R₁is (C₂-C₄)alkyl. In one embodiment of a compound of formula (IV), R₁ isisopropyl. In one embodiment of a compound of formula (IV), R₂ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (IV), R₂ isisopropyl. In one embodiment of a compound of formula (IV), R₃ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (IV), R₃ isisopropyl.

In one embodiment, provided herein is a compound of formula (II-A):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R′, R₁, R₂, and R₃ are each as defined herein.

In one embodiment of a compound of formula (II-A), R₁ is (C₁-C₄)alkyl.In one embodiment of a compound of formula (II-A), R₁ is methyl, ethyl,or isopropyl. In one embodiment of a compound of formula (II-A), R₂ ishydrogen, or (C₁-C₄)alkyl. In one embodiment of a compound of formula(II-A), R₂ is methyl, isopropyl, or tert-butyl. In one embodiment of acompound of formula (II-A), R₃ is (C₁-C₄)alkyl. In one embodiment of acompound of formula (II-A), R₃ is methyl, ethyl or isopropyl.

In one embodiment, provided herein is a compound of formula (II-A):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH;

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

R₁, R₂, and R₃ are independently (C₂-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a) and R_(b) together form a 3 to 10membered ring.

In one embodiment of a compound of formula (II-A), X is NH, and Y isS(O)₂. In another embodiment of a compound of formula (II-A), X isS(O)₂, and Y is NH.

In one embodiment of a compound of formula (II-A), R′ is hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (II-A), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (II-A), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy,wherein the alkyl and alkoxyl are each optionally substituted with oneor more halogen. In one embodiment of a compound of formula (II-A), R′is hydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃. In one embodiment ofa compound of formula (II-A), R′ is hydrogen or (C₁-C₄)alkyl. In oneembodiment of a compound of formula (II-A), R′ is hydrogen or methyl. Inone embodiment of a compound of formula (II-A), R′ is hydrogen. Inanother embodiment of a compound of formula (II-A), R′ is methyl. In yetanother embodiment of a compound of formula (II-A), R′ is Cl.

In one embodiment of a compound of formula (II-A), R₁, R₂, and R₃ areindependently (C₂-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (II-A), R₁is (C₂-C₄)alkyl. In one embodiment of a compound of formula (II-A), R₁is isopropyl. In one embodiment of a compound of formula (II-A), R₂ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (II-A), R₂ isisopropyl. In one embodiment of a compound of formula (II-A), R₃ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (II-A), R₃ isisopropyl.

In one embodiment, provided herein is a compound of formula (II-A-1):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R′, R₁, R₂, and R₃ are each as defined herein.

In one embodiment of a compound of formula (II-A-1), R₁ is (C₁-C₄)alkyl.In one embodiment of a compound of formula (II-A-1), R₁ is methyl,ethyl, or isopropyl. In one embodiment of a compound of formula(II-A-1), R₂ is hydrogen, or (C₁-C₄)alkyl. In one embodiment of acompound of formula (II-A-1), R₂ is methyl, isopropyl, or tert-butyl. Inone embodiment of a compound of formula (II-A-1), R₃ is (C₁-C₄)alkyl. Inone embodiment of a compound of formula (II-A-1), R₃ is methyl, ethyl orisopropyl.

In one embodiment, provided herein is a compound of formula (II-A-1):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH;

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

R₁, R₂, and R₃ are independently (C₂-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a). and R_(b) together form a 3 to 10membered ring.

In one embodiment of a compound of formula (II-A-1), X is NH, and Y isS(O)₂. In another embodiment of a compound of formula (II-A-1), X isS(O)₂, and Y is NH.

In one embodiment of a compound of formula (II-A-1), R′ is hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (II-A-1), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (II-A-1), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or(C₁-C₄)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (II-A-1), R′ is hydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃.In one embodiment of a compound of formula (II-A-1), R′ is hydrogen or(C₁-C₄)alkyl. In one embodiment of a compound of formula (II-A-1), R′ ishydrogen or methyl. In one embodiment of a compound of formula (II-A-1),R′ is hydrogen. In another embodiment of a compound of formula (II-A-1),R′ is methyl. In yet another embodiment of a compound of formula(II-A-1), R′ is Cl.

In one embodiment of a compound of formula (II-A-1), R₁, R₂, and R₃ areindependently (C₂-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (II-A-1),R₁ is (C₂-C₄)alkyl. In one embodiment of a compound of formula (II-A-1),R₁ is isopropyl. In one embodiment of a compound of formula (II-A-1), R₂is (C₂-C₄)alkyl. In one embodiment of a compound of formula (II-A-1), R₂is isopropyl. In one embodiment of a compound of formula (II-A-1), R₃ is(C₂-C₄)alkyl. In one embodiment of a compound of formula (II-A-1), R₃ isisopropyl.

In one embodiment, provided herein is a compound of formula (III-A-1):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R′, R₁, R₂, and R₃ are each as defined herein.

In one embodiment of a compound of formula (III-A-1), R₁ is(C₁-C₄)alkyl. In one embodiment of a compound of formula (III-A-1), R₁is methyl, ethyl, or isopropyl. In one embodiment of a compound offormula (III-A-1), R₂ is hydrogen, or (C₁-C₄)alkyl. In one embodiment ofa compound of formula (III-A-1), R₂ is methyl, isopropyl, or tert-butyl.In one embodiment of a compound of formula (III-A-1), R₃ is(C₁-C₄)alkyl. In one embodiment of a compound of formula (III-A-1), R₃is methyl, ethyl or isopropyl.

In one embodiment, provided herein is a compound of formula (III-A-1):

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein:

X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH;

R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a),C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a),S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy,(C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, whereinthe alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl,and cycloalkyloxy are each optionally substituted with one or morehalogen;

R₁, R₂, and R₃ are independently (C₂-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionallysubstituted with one or more halogen; and

R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl,(C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7membered)heterocyclyl; or R_(a). and R_(b) together form a 3 to 10membered ring.

In one embodiment of a compound of formula (III-A-1), X is NH, and Y isS(O)₂. In another embodiment of a compound of formula (III-A-1), X isS(O)₂, and Y is NH.

In one embodiment of a compound of formula (III-A-1), R′ is hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkylor (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are eachoptionally substituted with one or more halogen. In one embodiment of acompound of formula (III-A-1), R′ is hydrogen, halogen, (C₁-C₈)alkyl, or(C₁-C₈)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (III-A-1), R′ is hydrogen, halogen, (C₁-C₄)alkyl, or(C₁-C₄)alkoxy, wherein the alkyl and alkoxyl are each optionallysubstituted with one or more halogen. In one embodiment of a compound offormula (III-A-1), R′ is hydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, orOCF₃. In one embodiment of a compound of formula (III-A-1), R′ ishydrogen or (C₁-C₄)alkyl. In one embodiment of a compound of formula(III-A-1), R′ is hydrogen or methyl. In one embodiment of a compound offormula (III-A-1), R′ is hydrogen. In another embodiment of a compoundof formula (III-A-1), R′ is methyl. In yet another embodiment of acompound of formula (III-A-1), R′ is Cl.

In one embodiment of a compound of formula (III-A-1), R₁, R₂, and R₃ areindependently (C₂-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl. In one embodiment of a compound of formula (III-A-1),R₁ is (C₂-C₄)alkyl. In one embodiment of a compound of formula(III-A-1), R₁ is isopropyl. In one embodiment of a compound of formula(III-A-1), R₂ is (C₂-C₄)alkyl. In one embodiment of a compound offormula (III-A-1), R₂ is isopropyl. In one embodiment of a compound offormula (III-A-1), R₃ is (C₂-C₄)alkyl. In one embodiment of a compoundof formula (III-A-1), R₃ is isopropyl.

In one embodiment, specific examples of the compound of formula(III-A-1) include, but are not limited to, the following:

All of the combinations of the above embodiments are encompassed by thisinvention.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it. Where thecompound provided herein contains an alkenyl or alkenylene group, thecompound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are inter-convertible, the compoundmay exist as a single tautomer or a mixture of tautomers. This can takethe form of proton tautomerism in the compound that contains, forexample, an imino, keto, or oxime group; or so-called valencetautomerism in the compound that contain an aromatic moiety. It followsthat a single compound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. In someinstances, for compounds that undergo epimerization in vivo, one ofskill in the art will recognize that administration of a compound in its(R) form is equivalent to administration of the compound in its (S)form. Conventional techniques for the preparation/isolation ofindividual enantiomers include synthesis from a suitable optically pureprecursor, asymmetric synthesis from achiral starting materials, orresolution of an enantiomeric mixture, for example, by chiralchromatography, recrystallization, resolution, diastereomeric saltformation, or derivatization into diastereomeric adducts followed byseparation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, e.g.,Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook ofPharmaceutical Salts, Properties, and Use, Stahl and Wermuth, ed.;Wiley-VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

In certain embodiments, the compounds provided herein arepharmacologically acceptable salts of the compounds with one or more ofhydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic,and isoethonic acids; or with one or more of potassium carbonate, sodiumor potassium hydroxide, ammonia, triethylamine, and triethanolamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See, e.g., Harper, Progress in Drug Research 1962,4, 221-294; Morozowich et al. in Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs, Roche ed., APHA Acad. Pharm. Sci. 1977;Bioreversible Carriers in Drug in Drug Design, Theory and Application,Roche ed., APHA Acad. Pharm. Sci. 1987; Design of Prodrugs, Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in Transport Processes inPharmaceutical Systems, Amidon et al., ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane & Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

C. METHODS OF SYNTHESIS

Schemes below provide exemplary synthetic methods for the preparation ofthe compounds provided herein. One of ordinary skill in the art willunderstand that similar methods may be employed to prepare the compoundsprovided herein. In other words, one of ordinary skill in the art willrecognize that suitable adjustments to reagents, protecting groups,reaction conditions, and reaction sequences may be employed to prepare adesired embodiment. The reaction may be scaled upwards or downwards tosuit the amount of material to be prepared. In one embodiment, thecompounds provided herein may be prepared by the procedures andtechniques similar to those disclosed in the Examples. In oneembodiment, the compounds provided herein may be prepared by proceduresand techniques known in the art for coupling sulfonyl chlorides withamines. In one embodiment, the sulfonyl chlorides are prepared byprocedures and techniques known in the art.

In one embodiment, the starting material used to prepare the compoundsprovided herein may be obtained from a commercial source. In oneembodiment, the starting material used to prepare the compounds providedherein may be prepared following the procedures or conditions known inthe art.

In one embodiment, the compounds provided herein may be preparedfollowing Scheme 1. In one embodiment, the compounds are prepared byadding an excess or approximately equal molar amount of the sulfonylchloride to a solution of a suitable amine, and a base, such as, e.g.,N,N-diisopropylethylamine, in a solvent, such as, e.g., dichloromethane.In one embodiment, the compounds are prepared by adding an excess orapproximately equal molar amount of the sulfonyl chloride to a solutionof a suitable amine in a basic solvent, such as, e.g., pyridine. In oneembodiment, after the reaction is stirred at room temperature until thereaction is complete, as monitored by, e.g., thin layer chromatography.In one embodiment, the reaction undergoes an aqueous workup washing withdilute HCl, followed by saturated aqueous NaHCO₃ solution and brine. Inone embodiment, the reaction undergoes an aqueous workup washing with0.1N HCl, followed by 0.1 N NaOH solution and brine. In one embodiment,after the aqueous workup the reaction mixture is dried over MgSO₄ andconcentrated. In one embodiment, the compound may be further purified bycolumn chromatography or by passing through a silica gel plug using aneluent, such as ethyl acetate/hexanes. In one embodiment, the compoundmay be further purified using trituration with hexanes. In oneembodiment, the compound is analyzed by LCMS. In one embodiment, thecompound is analyzed by ¹H NMR.

In one embodiment, a compound of formula (I), wherein X is NH and Y isS(O)₂, may be prepared following Scheme 1, wherein the intermediates I-1and I-2 may be obtained from a commercial source or prepared followingprocedures known in the art. R, R′, and n are as defined hereinelsewhere. In one embodiment, the base used in the reaction of Scheme 1is triethylamine or diisopropylethylamine. In one embodiment, thereaction of Scheme 1 is carried out in a basic solvent. In oneembodiment, the reaction of Scheme 1 is carried out in dry pyridine.

In one embodiment, a compound of formula (I), wherein X is S(O)₂ and Yis NH, may be prepared following Scheme 2, wherein the intermediates I-3and I-4 may be obtained from a commercial source or prepared followingprocedures known in the art. R, R′, and n are as defined hereinelsewhere. In one embodiment, the base used in the reaction of Scheme 2is triethylamine or diisopropylethylamine. In one embodiment, thereaction of Scheme 2 is carried out in a basic solvent. In oneembodiment, the reaction of Scheme 2 is carried out in dry pyridine.

In one embodiment, the compounds provided herein may be made by theprocedures and techniques disclosed in the Examples, as well as knownorganic synthesis techniques for coupling sulfonyl chlorides and amines.

D. PHARMACEUTICAL COMPOSITIONS

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound of formula (I) as defined herein elsewhere, or anenantiomer, a mixture of enantiomers or a mixture of diastereomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof, and at least one pharmaceutically acceptable excipient,adjuvant, carrier, buffer, or stabiliser.

In one embodiment, the pharmaceutically acceptable excipient, adjuvant,carrier, buffer, or stabiliser is non-toxic and does not interfere withthe efficacy of the active ingredient. The precise nature of the carrieror other material will depend on the route of administration, which maybe oral or by injection, such as cutaneous, subcutaneous, or intravenousinjection.

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, and one or morepharmaceutically acceptable excipients or carriers. The pharmaceuticalcompositions provided herein that are formulated for oral administrationmay be in tablet, capsule, powder, or liquid form. A tablet may comprisea solid carrier or an adjuvant. Liquid pharmaceutical compositionsgenerally comprise a liquid carrier such as water, petroleum, animal orvegetable oils, or mineral oil or synthetic oil. Physiological salinesolution, dextrose or other saccharide solution, or glycols such asethylene glycol, propylene glycol, or polyethylene glycol may beincluded. A capsule may comprise a solid carrier such as gelatin.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, and one or morepharmaceutically acceptable excipients or carriers. Where pharmaceuticalcompositions may be formulated for intravenous, cutaneous orsubcutaneous injection, the active ingredient will be in the form of aparenterally acceptable aqueous solution, which is pyrogen-free and hasa suitable pH, isotonicity, and stability. Those of relevant skill inthe art are well able to prepare suitable solutions using, for example,isotonic vehicles, such as Sodium Chloride injection, Ringer'sinjection, or Lactated Ringer's injection. Preservatives, stabilisers,buffers, antioxidants, and/or other additives may be included asrequired.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers.

In one embodiment, the pharmaceutical compositions can also beformulated as modified release dosage forms, including delayed-,extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-and fast-, targeted-, programmed-release, and gastric retention dosageforms. These dosage forms can be prepared according to conventionalmethods and techniques known to those skilled in the art (see, e.g.,Remington: The Science and Practice of Pharmacy, supra; Modified-ReleaseDrug Delivery Technology, 2nd Ed., Rathbone et al., eds., Marcel Dekker,Inc.: New York, N. Y., 2008).

In one embodiment, the pharmaceutical compositions provided herein canbe provided in a unit-dosage form or multiple-dosage form. A unit-dosageform, as used herein, refers to physically discrete a unit suitable foradministration to a human and animal subject, and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof an active ingredient(s) sufficient to produce the desired therapeuticeffect, in association with the required pharmaceutical carriers orexcipients. Examples of a unit-dosage form include an ampoule, syringe,and individually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

In one embodiment, the pharmaceutical compositions provided herein canbe administered at once, or multiple times at intervals of time. It isunderstood that the precise dosage and duration of treatment may varywith the age, weight, and condition of the patient being treated, andmay be determined empirically using known testing protocols or byextrapolation from in vivo or in vitro test or diagnostic data. It isfurther understood that for any particular individual, specific dosageregimens should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the formulations.

In another embodiment, the pharmaceutical compositions provided hereinfurther comprise one or more chemotherapeutic agents as defined herein.

In yet another embodiment, provided herein is the use of a compound offormula (I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, in the manufacture of a medicament for thetreatment of one or more disorders disclosed herein. In certainembodiments, the medicament is in tablet, capsule, powder, or liquidform. In certain embodiments, the medicament is formulated as describedherein.

1. Oral Administration

In one embodiment, the pharmaceutical compositions provided herein fororal administration can be provided in solid, semisolid, or liquiddosage forms for oral administration. As used herein, oraladministration also includes buccal, lingual, and sublingualadministration. Suitable oral dosage forms include, but are not limitedto, tablets, fastmelts, chewable tablets, capsules, pills, strips,troches, lozenges, pastilles, cachets, pellets, medicated chewing gum,bulk powders, effervescent or non-effervescent powders or granules, oralmists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs,and syrups. In addition to the active ingredient(s), the pharmaceuticalcompositions can contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, flavoring agents,emulsifying agents, suspending and dispersing agents, preservatives,solvents, non-aqueous liquids, organic acids, and sources of carbondioxide.

In one embodiment, binders or granulators impart cohesiveness to atablet to ensure the tablet remaining intact after compression. Suitablebinders or granulators include, but are not limited to, starches, suchas corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses,and lactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

In one embodiment, suitable diluents include, but are not limited to,dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose,inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, andpowdered sugar. Certain diluents, such as mannitol, lactose, sorbitol,sucrose, and inositol, when present in sufficient quantity, can impartproperties to some compressed tablets that permit disintegration in themouth by chewing. Such compressed tablets can be used as chewabletablets. The amount of a diluent in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art.

In one embodiment, suitable disintegrants include, but are not limitedto, agar; bentonite; celluloses, such as methylcellulose andcarboxymethylcellulose; wood products; natural sponge; cation-exchangeresins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp;cross-linked celluloses, such as croscarmellose; cross-linked polymers,such as crospovidone; cross-linked starches; calcium carbonate;microcrystalline cellulose, such as sodium starch glycolate; polacrilinpotassium; starches, such as corn starch, potato starch, tapioca starch,and pre-gelatinized starch; clays; aligns; and mixtures thereof. Theamount of a disintegrant in the pharmaceutical compositions providedherein varies upon the type of formulation, and is readily discernibleto those of ordinary skill in the art. The amount of a disintegrant inthe pharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

In one embodiment, suitable lubricants include, but are not limited to,calcium stearate; magnesium stearate; mineral oil; light mineral oil;glycerin; sorbitol; mannitol; glycols, such as glycerol behenate andpolyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc;hydrogenated vegetable oil, including peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zincstearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silicaor silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, Md.)and CAB-O-SIL® (Cabot Co. of Boston, Mass.); and mixtures thereof. Thepharmaceutical compositions provided herein may contain about 0.1 toabout 5% by weight of a lubricant.

In one embodiment, suitable glidants include, but are not limited to,colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), andasbestos-free talc. Suitable coloring agents include, but are notlimited to, any of the approved, certified, water soluble FD&C dyes, andwater insoluble FD&C dyes suspended on alumina hydrate, and color lakesand mixtures thereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

In one embodiment, the pharmaceutical compositions provided herein fororal administration can be provided as compressed tablets, tablettriturates, chewable lozenges, rapidly dissolving tablets, multiplecompressed tablets, or enteric-coating tablets, sugar-coated, orfilm-coated tablets. Enteric-coated tablets are compressed tabletscoated with substances that resist the action of stomach acid butdissolve or disintegrate in the intestine, thus protecting the activeingredients from the acidic environment of the stomach. Enteric-coatingsinclude, but are not limited to, fatty acids, fats, phenyl salicylate,waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.Sugar-coated tablets are compressed tablets surrounded by a sugarcoating, which may be beneficial in covering up objectionable tastes orodors and in protecting the tablets from oxidation. Film-coated tabletsare compressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

In one embodiment, the tablet dosage forms can be prepared from theactive ingredient in powdered, crystalline, or granular forms, alone orin combination with one or more carriers or excipients described herein,including binders, disintegrants, controlled-release polymers,lubricants, diluents, and/or colorants. Flavoring and sweetening agentsare especially useful in the formation of chewable tablets and lozenges.

In one embodiment, the pharmaceutical compositions provided herein fororal administration can be provided as soft or hard capsules, which canbe made from gelatin, methylcellulose, starch, or calcium alginate. Thehard gelatin capsule, also known as the dry-filled capsule (DFC),consists of two sections, one slipping over the other, thus completelyenclosing the active ingredient. The soft elastic capsule (SEC) is asoft, globular shell, such as a gelatin shell, which is plasticized bythe addition of glycerin, sorbitol, or a similar polyol. The softgelatin shells may contain a preservative to prevent the growth ofmicroorganisms. Suitable preservatives are those as described herein,including methyl- and propyl-parabens, and sorbic acid. The liquid,semisolid, and solid dosage forms provided herein may be encapsulated ina capsule. Suitable liquid and semisolid dosage forms include solutionsand suspensions in propylene carbonate, vegetable oils, ortriglycerides. Capsules containing such solutions can be prepared asdescribed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. Thecapsules may also be coated as known by those of skill in the art inorder to modify or sustain dissolution of the active ingredient.

In one embodiment, the pharmaceutical compositions provided herein fororal administration can be provided in liquid and semisolid dosageforms, including emulsions, solutions, suspensions, elixirs, and syrups.An emulsion is a two-phase system, in which one liquid is dispersed inthe form of small globules throughout another liquid, which can beoil-in-water or water-in-oil. Emulsions may include a pharmaceuticallyacceptable non-aqueous liquid or solvent, emulsifying agent, andpreservative. Suspensions may include a pharmaceutically acceptablesuspending agent and preservative. Aqueous alcoholic solutions mayinclude a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; anda water-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

In one embodiment, other useful liquid and semisolid dosage formsinclude, but are not limited to, those containing the activeingredient(s) provided herein, and a dialkylated mono- or poly-alkyleneglycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme,polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethylether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750refer to the approximate average molecular weight of the polyethyleneglycol. These formulations can further comprise one or moreantioxidants, such as butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite,thiodipropionic acid and its esters, and dithiocarbamates.

In one embodiment, the pharmaceutical compositions provided herein fororal administration can be also provided in the forms of liposomes,micelles, microspheres, or nanosystems. Micellar dosage forms can beprepared as described in U.S. Pat. No. 6,350,458.

In one embodiment, the pharmaceutical compositions provided herein fororal administration can be provided as non-effervescent or effervescent,granules and powders, to be reconstituted into a liquid dosage form.Pharmaceutically acceptable carriers and excipients used in thenon-effervescent granules or powders may include diluents, sweeteners,and wetting agents. Pharmaceutically acceptable carriers and excipientsused in the effervescent granules or powders may include organic acidsand a source of carbon dioxide.

In one embodiment, coloring and flavoring agents can be used in all ofthe above dosage forms.

In one embodiment, the pharmaceutical compositions provided herein fororal administration can be formulated as immediate or modified releasedosage forms, including delayed-, sustained, pulsed-, controlled,targeted-, and programmed-release forms.

2. Parenteral Administration

In one embodiment, the pharmaceutical compositions provided herein canbe administered parenterally by injection, infusion, or implantation,for local or systemic administration. Parenteral administration, as usedherein, include intravenous, intraarterial, intraperitoneal,intrathecal, intraventricular, intraurethral, intrasternal,intracranial, intramuscular, intrasynovial, intravesical, andsubcutaneous administration.

In one embodiment, the pharmaceutical compositions provided herein forparenteral administration can be formulated in any dosage forms that aresuitable for parenteral administration, including solutions,suspensions, emulsions, micelles, liposomes, microspheres, nanosystems,and solid forms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, e.g., Remington: The Science and Practice of Pharmacy, supra).

In one embodiment, the pharmaceutical compositions intended forparenteral administration can include one or more pharmaceuticallyacceptable carriers and excipients, including, but not limited to,aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, cryoprotectants, lyoprotectants,thickening agents, pH adjusting agents, and inert gases.

In one embodiment, suitable aqueous vehicles include, but are notlimited to, water, saline, physiological saline or phosphate bufferedsaline (PBS), sodium chloride injection, Ringers injection, isotonicdextrose injection, sterile water injection, dextrose and lactatedRingers injection. Suitable non-aqueous vehicles include, but are notlimited to, fixed oils of vegetable origin, castor oil, corn oil,cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil,sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenatedsoybean oil, and medium-chain triglycerides of coconut oil, and palmseed oil. Suitable water-miscible vehicles include, but are not limitedto, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g.,polyethylene glycol 300 and polyethylene glycol 400), propylene glycol,glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethylsulfoxide.

In one embodiment, suitable antimicrobial agents or preservativesinclude, but are not limited to, phenols, cresols, mercurials, benzylalcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates,thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl-and propyl-parabens, and sorbic acid. Suitable isotonic agents include,but are not limited to, sodium chloride, glycerin, and dextrose.Suitable buffering agents include, but are not limited to, phosphate andcitrate. Suitable antioxidants are those as described herein, includingbisulfite and sodium metabisulfite. Suitable local anesthetics include,but are not limited to, procaine hydrochloride. Suitable suspending anddispersing agents are those as described herein, including sodiumcarboxymethylcelluose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable emulsifying agents are those describedherein, including polyoxyethylene sorbitan monolaurate, polyoxyethylenesorbitan monooleate 80, and triethanolamine oleate. Suitablesequestering or chelating agents include, but are not limited to EDTA.Suitable pH adjusting agents include, but are not limited to, sodiumhydroxide, hydrochloric acid, citric acid, and lactic acid. Suitablecomplexing agents include, but are not limited to, cyclodextrins,including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin,sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin(CAPTISOL®, CyDex, Lenexa, Kans.).

In one embodiment, when the pharmaceutical compositions provided hereinare formulated for multiple dosage administration, the multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

In one embodiment, the pharmaceutical compositions provided herein forparenteral administration can be formulated as immediate or modifiedrelease dosage forms, including delayed-, sustained, pulsed-,controlled, targeted-, and programmed-release forms.

In one embodiment, the pharmaceutical compositions provided herein forparenteral administration can be formulated as a suspension, solid,semi-solid, or thixotropic liquid, for administration as an implanteddepot. In one embodiment, the pharmaceutical compositions providedherein are dispersed in a solid inner matrix, which is surrounded by anouter polymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

In one embodiment, suitable inner matrixes include, but are not limitedto, polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

In one embodiment, suitable outer polymeric membranes include but arenot limited to, polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

3. Topical Administration

In one embodiment, the pharmaceutical compositions provided herein canbe administered topically to the skin, orifices, or mucosa. The topicaladministration, as used herein, includes (intra)dermal, conjunctival,intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal,vaginal, urethral, respiratory, and rectal administration.

In one embodiment, the pharmaceutical compositions provided herein canbe formulated in any dosage forms that are suitable for topicaladministration for local or systemic effect, including emulsions,solutions, suspensions, creams, gels, hydrogels, ointments, dustingpowders, dressings, elixirs, lotions, suspensions, tinctures, pastes,foams, films, aerosols, irrigations, sprays, suppositories, bandages,and dermal patches. The topical formulation of the pharmaceuticalcompositions provided herein can also comprise liposomes, micelles,microspheres, nanosystems, and mixtures thereof.

In one embodiment, pharmaceutically acceptable carriers and excipientssuitable for use in the topical formulations provided herein include,but are not limited to, aqueous vehicles, water-miscible vehicles,non-aqueous vehicles, antimicrobial agents or preservatives against thegrowth of microorganisms, stabilizers, solubility enhancers, isotonicagents, buffering agents, antioxidants, local anesthetics, suspendingand dispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

In one embodiment, the pharmaceutical compositions can also beadministered topically by electroporation, iontophoresis, phonophoresis,sonophoresis, or microneedle or needle-free injection, such asPOWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (BiojectMedical Technologies Inc., Tualatin, Oreg.).

In one embodiment, the pharmaceutical compositions provided herein canbe provided in the forms of ointments, creams, and gels. Suitableointment vehicles include oleaginous or hydrocarbon vehicles, includinglard, benzoinated lard, olive oil, cottonseed oil, and other oils, whitepetrolatum; emulsifiable or absorption vehicles, such as hydrophilicpetrolatum, hydroxystearin sulfate, and anhydrous lanolin;water-removable vehicles, such as hydrophilic ointment; water-solubleointment vehicles, including polyethylene glycols of varying molecularweight; emulsion vehicles, either water-in-oil (W/O) emulsions oroil-in-water (O/W) emulsions, including cetyl alcohol, glycerylmonostearate, lanolin, and stearic acid (see, e.g., Remington: TheScience and Practice of Pharmacy, supra). These vehicles are emollientbut generally require addition of antioxidants and preservatives.

In one embodiment, suitable cream base can be oil-in-water orwater-in-oil. Suitable cream vehicles may be water-washable, and containan oil phase, an emulsifier, and an aqueous phase. The oil phase is alsocalled the “internal” phase, which is generally comprised of petrolatumand a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phaseusually, although not necessarily, exceeds the oil phase in volume, andgenerally contains a humectant. The emulsifier in a cream formulationmay be a nonionic, anionic, cationic, or amphoteric surfactant.

In one embodiment, gels are semisolid, suspension-type systems.Single-phase gels contain organic macromolecules distributedsubstantially uniformly throughout the liquid carrier. Suitable gellingagents include, but are not limited to, crosslinked acrylic acidpolymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

In one embodiment, the pharmaceutical compositions provided herein canbe administered rectally, urethrally, vaginally, or perivaginally in theforms of suppositories, pessaries, bougies, poultices or cataplasm,pastes, powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

In one embodiment, rectal, urethral, and vaginal suppositories are solidbodies for insertion into body orifices, which are solid at ordinarytemperatures but melt or soften at body temperature to release theactive ingredient(s) inside the orifices. Pharmaceutically acceptablecarriers utilized in rectal and vaginal suppositories include bases orvehicles, such as stiffening agents, which produce a melting point inthe proximity of body temperature, when formulated with thepharmaceutical compositions provided herein; and antioxidants asdescribed herein, including bisulfite and sodium metabisulfite. Suitablevehicles include, but are not limited to, cocoa butter (theobroma oil),glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti,paraffin, white and yellow wax, and appropriate mixtures of mono-, di-and triglycerides of fatty acids, and hydrogels, such as polyvinylalcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinationsof the various vehicles can also be used. Rectal and vaginalsuppositories may be prepared by compressing or molding. The typicalweight of a rectal and vaginal suppository is about 2 to about 3 g.

In one embodiment, the pharmaceutical compositions provided herein canbe administered ophthalmically in the forms of solutions, suspensions,ointments, emulsions, gel-forming solutions, powders for solutions,gels, ocular inserts, and implants.

In one embodiment, the pharmaceutical compositions provided herein canbe administered intranasally or by inhalation to the respiratory tract.The pharmaceutical compositions can be provided in the form of anaerosol or solution for delivery using a pressurized container, pump,spray, atomizer, such as an atomizer using electrohydrodynamics toproduce a fine mist, or nebulizer, alone or in combination with asuitable propellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

In one embodiment, solutions or suspensions for use in a pressurizedcontainer, pump, spray, atomizer, or nebulizer can be formulated tocontain ethanol, aqueous ethanol, or a suitable alternative agent fordispersing, solubilizing, or extending release of the active ingredientprovided herein; a propellant as solvent; and/or a surfactant, such assorbitan trioleate, oleic acid, or an oligolactic acid.

In one embodiment, the pharmaceutical compositions provided herein canbe micronized to a size suitable for delivery by inhalation, such asabout 50 micrometers or less, or about 10 micrometers or less. Particlesof such sizes can be prepared using a comminuting method known to thoseskilled in the art, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenization, or spray drying.

In one embodiment, capsules, blisters, and cartridges for use in aninhaler or insufflator can be formulated to contain a powder mix of thepharmaceutical compositions provided herein; a suitable powder base,such as lactose or starch; and a performance modifier, such asl-leucine, mannitol, or magnesium stearate. The lactose may be anhydrousor in the form of the monohydrate. Other suitable excipients or carriersinclude, but are not limited to, dextran, glucose, maltose, sorbitol,xylitol, fructose, sucrose, and trehalose. The pharmaceuticalcompositions provided herein for inhaled/intranasal administration canfurther comprise a suitable flavor, such as menthol and levomenthol;and/or sweeteners, such as saccharin and saccharin sodium.

In one embodiment, the pharmaceutical compositions provided herein fortopical administration can be formulated to be immediate release ormodified release, including delayed-, sustained-, pulsed-, controlled-,targeted, and programmed release.

4. Modified Release

In one embodiment, the pharmaceutical compositions provided herein canbe formulated as a modified release dosage form. As used herein, theterm “modified release” refers to a dosage form in which the rate orplace of release of the active ingredient(s) is different from that ofan immediate dosage form when administered by the same route. Modifiedrelease dosage forms include, but are not limited to, delayed-,extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-and fast-, targeted-, programmed-release, and gastric retention dosageforms. The pharmaceutical compositions in modified release dosage formscan be prepared using a variety of modified release devices and methodsknown to those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

(a) Matrix Controlled Release Devices

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form can be fabricated using a matrix controlledrelease device known to those skilled in the art (see, e.g., Takada etal. in Encyclopedia of Controlled Drug Delivery, Vol. 2, Mathiowitz Ed.,Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

In one embodiment, materials useful in forming an erodible matrixinclude, but are not limited to, chitin, chitosan, dextran, andpullulan; gum agar, gum arabic, gum karaya, locust bean gum, gumtragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, andscleroglucan; starches, such as dextrin and maltodextrin; hydrophiliccolloids, such as pectin; phosphatides, such as lecithin; alginates;propylene glycol alginate; gelatin; collagen; cellulosics, such as ethylcellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose(CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose(HPC), cellulose acetate (CA), cellulose propionate (CP), cellulosebutyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropylmethyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl celluloseacetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In one embodiment, in a matrix controlled release system, the desiredrelease kinetics can be controlled, for example, via the polymer typeemployed, the polymer viscosity, the particle sizes of the polymerand/or the active ingredient(s), the ratio of the active ingredient(s)versus the polymer, and other excipients or carriers in thecompositions.

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form can be prepared by methods known to thoseskilled in the art, including direct compression, dry or wet granulationfollowed by compression, and melt-granulation followed by compression.

(b) Osmotic Controlled Release Devices

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form can be fabricated using an osmoticcontrolled release device, including, but not limited to, one-chambersystem, two-chamber system, asymmetric membrane technology (AMT), andextruding core system (ECS). In general, such devices have at least twocomponents: (a) a core which contains an active ingredient; and (b) asemipermeable membrane with at least one delivery port, whichencapsulates the core. The semipermeable membrane controls the influx ofwater to the core from an aqueous environment of use so as to cause drugrelease by extrusion through the delivery port(s).

In one embodiment, in addition to the active ingredient(s), the core ofthe osmotic device optionally includes an osmotic agent, which creates adriving force for transport of water from the environment of use intothe core of the device. One class of osmotic agents is water-swellablehydrophilic polymers, which are also referred to as “osmopolymers” and“hydrogels.” Suitable water-swellable hydrophilic polymers as osmoticagents include, but are not limited to, hydrophilic vinyl and acrylicpolymers, polysaccharides such as calcium alginate, polyethylene oxide(PEO), polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

In one embodiment, the other class of osmotic agents is osmogens, whichare capable of imbibing water to affect an osmotic pressure gradientacross the barrier of the surrounding coating. Suitable osmogensinclude, but are not limited to, inorganic salts, such as magnesiumsulfate, magnesium chloride, calcium chloride, sodium chloride, lithiumchloride, potassium sulfate, potassium phosphates, sodium carbonate,sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate;sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose,mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organicacids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid,maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid,glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid;urea; and mixtures thereof

In one embodiment, osmotic agents of different dissolution rates can beemployed to influence how rapidly the active ingredient(s) is initiallydelivered from the dosage form. For example, amorphous sugars, such asMANNOGEM™ EZ (SPI Pharma, Lewes, Del.) can be used to provide fasterdelivery during the first couple of hours to promptly produce thedesired therapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

In one embodiment, the core can also include a wide variety of otherexcipients and carriers as described herein to enhance the performanceof the dosage form or to promote stability or processing.

In one embodiment, materials useful in forming the semipermeablemembrane include various grades of acrylics, vinyls, ethers, polyamides,polyesters, and cellulosic derivatives that are water-permeable andwater-insoluble at physiologically relevant pHs, or are susceptible tobeing rendered water-insoluble by chemical alteration, such ascrosslinking Examples of suitable polymers useful in forming thecoating, include plasticized, unplasticized, and reinforced celluloseacetate (CA), cellulose diacetate, cellulose triacetate, CA propionate,cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate,CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate(CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CAethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

In one embodiment, semipermeable membrane can also be a hydrophobicmicroporous membrane, wherein the pores are substantially filled with agas and are not wetted by the aqueous medium but are permeable to watervapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic butwater-vapor permeable membrane are typically composed of hydrophobicpolymers such as polyalkenes, polyethylene, polypropylene,polytetrafluoroethylene, polyacrylic acid derivatives, polyethers,polysulfones, polyethersulfones, polystyrenes, polyvinyl halides,polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, andsynthetic waxes.

In one embodiment, the delivery port(s) on the semipermeable membranecan be formed post-coating by mechanical or laser drilling. Deliveryport(s) can also be formed in situ by erosion of a plug of water-solublematerial or by rupture of a thinner portion of the membrane over anindentation in the core. In addition, delivery ports can be formedduring coating process, as in the case of asymmetric membrane coatingsof the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.

In one embodiment, the total amount of the active ingredient(s) releasedand the release rate can substantially by modulated via the thicknessand porosity of the semipermeable membrane, the composition of the core,and the number, size, and position of the delivery ports.

In one embodiment, the pharmaceutical compositions in an osmoticcontrolled-release dosage form can further comprise additionalconventional excipients or carriers as described herein to promoteperformance or processing of the formulation.

In one embodiment, the osmotic controlled-release dosage forms can beprepared according to conventional methods and techniques known to thoseskilled in the art (see, e.g., Remington: The Science and Practice ofPharmacy, supra; Santus & Baker, J. Controlled Release 1995, 35, 1-21;Verma et al., Drug Development and Industrial Pharmacy 2000, 26,695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, e.g., U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

(c) Multiparticulate Controlled Release Devices

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form can be fabricated as a multiparticulatecontrolled release device, which comprises a multiplicity of particles,granules, or pellets, ranging from about 10 μm to about 3 mm, about 50μm to about 2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994;Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

In one embodiment, other excipients or carriers as described herein canbe blended with the pharmaceutical compositions to aid in processing andforming the multiparticulates. The resulting particles can themselvesconstitute the multiparticulate device or can be coated by variousfilm-forming materials, such as enteric polymers, water-swellable, andwater-soluble polymers. The multiparticulates can be further processedas a capsule or a tablet.

(d) Targeted Delivery

In one embodiment, the pharmaceutical compositions provided herein canalso be formulated to be targeted to a particular tissue, receptor, orother area of the body of the subject to be treated, includingliposome-, resealed erythrocyte-, and antibody-based delivery systems.Examples include, but are not limited to, those disclosed in U.S. Pat.Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570;6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534;5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

(e) Targeted Delivery with Special Carriers

In one embodiment, the pharmaceutical compositions provided herein canalso be formulated or engineered to be bound to a particular carrier,including but not limited to albumin, PEG (polyethylene glycol),PEGylated albumin polymers, PG (poly(l-glutamic acid)) polymers and suchas to form polymer-drug conjugates. Examples include, but are notlimited to, those disclosed in U.S. Pat. Nos. 5,977,163; 5,648,506;6,703,417; 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579;6,749,868; 6,753,006; 7,820,788; 7,923,536; 8,034,375; 8,138,229;8,268,348; and 8,314,156 each of which is incorporated herein byreference.

5. Kits

In one embodiment, provided herein are kits which, when used by themedical practitioner, can simplify the administration of appropriateamounts of active ingredients to a subject. In certain embodiments, thekit provided herein includes a container and a dosage form of a compoundprovided herein, including a single enantiomer or a mixture ofenantiomers or diastereomers thereof; or a pharmaceutically acceptablesalt, solvate, or prodrug thereof

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer or amixture of enantiomers or diastereomers thereof; or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, in a container comprisingone or more other therapeutic agent(s) described herein.

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise one or more second active ingredientsas described herein, or a pharmacologically active mutant or derivativethereof, or a combination thereof

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

In one embodiment, kits can further comprise cells or blood fortransplantation as well as pharmaceutically acceptable vehicles that canbe used to administer one or more active ingredients. For example, if anactive ingredient is provided in a solid form that must be reconstitutedfor parenteral administration, the kit can comprise a sealed containerof a suitable vehicle in which the active ingredient can be dissolved toform a particulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

In one embodiment, the compounds provided herein can also be provided asan article of manufacture using packaging materials well known to thoseof skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and5,033,252. Examples of pharmaceutical packaging materials include, butare not limited to, blister packs, bottles, tubes, inhalers, pumps,bags, vials, containers, syringes, and any packaging material suitablefor a selected formulation and intended mode of administration andtreatment.

E. METHODS OF USE

1. In Vitro Assays and In Vivo Assays

In one embodiment, provided herein is a method of inhibiting or reducingthe activity of eIF4E. In one embodiment, provided herein is a method ofdownregulating protein translation initiation with a compound providedherein, e.g., a compound of formula (I). In one embodiment, withoutbeing limited by a particular theory, the method comprises contacting acompound provided herein, e.g., a compound of formula (I), with one ormore molecular targets in the translation initiation complex eIF4F,which comprises eIF4E, eIF4G (a scaffold protein), and eIF4A (an RNAhelicase). In one embodiment, without being limited by a particulartheory, the method comprises disrupting the interaction between eIF4Eand the 7-methylguanosine 5′ cap with a compound provided herein, e.g.,a compound of formula (I). In one embodiment, the method provided hereincomprises selectively downregulating protein translation initiation witha compound provided herein, e.g., a compound of formula (I). In oneembodiment, the compound provided herein has minimal on-target toxicity.In one embodiment, the compound provided herein has a large therapeuticindex. In one embodiment, the compound provided herein inhibits cancergrowth while having minimal toxicity in normal cells.

In one embodiment, the compound selectively targets the proteintranslation pathway. In one embodiment, without being limited by aparticular theory, the compound selectively disrupts the eIF4F complex.

In one embodiment, provided herein are methods comprising the step ofcontacting a compound provided herein with one or more cells of acertain type of fibrosis including but not limited to organ specificfibrosis (heart, liver, lung, kidney, bone marrow, skin, pancreas),other forms of fibrosis (retroperitoneal, nephrogenic, and cystic), andconnective tissue disorders (atherosclerosis, cirrhosis, scleroderma,keloids, Crohn's disease, and endometriosis). In one embodiment,provided herein are methods comprising the step of contacting a compoundprovided herein with one or more cells of a certain type of cancer,including but not limited to, metastatic cancer, breast cancer (e.g.,triple negative breast cancer, ER+breast cancer, or ER−breast cancer),basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer,non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma,colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer(e.g., carcinoma, angiosarcoma, adenosarcoma), gastric cancer,gastroesophageal junction cancer, prostate cancer, cervical cancer,bladder cancer, head and neck cancer, lymphoma (e.g., mantle celllymphoma, diffuse large B-cell lymphoma), solid tumors that cannot beremoved by surgery, locally advanced solid tumors, metastatic solidtumors, leukemia (e.g., acute myeloid leukemia (AML), acutelymphoblastic leukemia (ALL), or chronic myeloid leukemia (CML)), orrecurrent or refractory tumors. In one embodiment, provided herein aremethods comprising the step of contacting a compound provided hereinwith one or more cells of a certain type of disorder, including but notlimited to, basal cell nevus syndrome (Gorlin syndrome). In oneembodiment, provided herein are methods comprising the step ofcontacting a compound provided herein with one or more cells of acertain type of disorder, including but not limited to, basal cellcarcinoma associated with Gorlin syndrome. In certain embodiments, themethods may be conducted in vivo, in vitro, and/or ex vivo. In certainembodiments, the methods may be conducted in an animal, e.g., mice orrats. In certain embodiments, the methods provided herein furthercomprise the step of implanting a certain cancer cell type (e.g., breastcancer) in an animal (e.g., mice or rats) using a method known in theart, followed by the step of treating the animal with a compoundprovided herein. The time between the implanting step and the treatmentstep may vary to allow the establishment and/or metastasis of cancer inthe animal.

In one embodiment, the compound provided herein modulates secretedcytokines from activated peripheral blood mononuclear cells (PBMCs) andaugments cytotoxicity in certain cancer cell lines, including, but notlimited to, MDA-MB-468 (triple negative breast cancer), XPA-1(pancreatic cancer), and Panc-1 (pancreatic cancer).

In one embodiment, provided herein is a method of inhibiting or reducingthe activity of cancer associated fibroblasts in the tumor stroma. Inone embodiment, the compound provided herein inhibits or reducesalpha-smooth muscle actin.

In one embodiment, the cells are sensitive to a compound providedherein, e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, wherein the EC₅₀ ofthe compound is less than about 0.001 μM, less than about 0.005 μM, lessthan about 0.01 μM, less than about 0.05 μM, less than about 0.1 μM,less than about 0.3 μM, less than about 0.5 μM, less than about 0.7 μM,less than about 1 μM, less than about 3 μM, less than about 5 μM, lessthan about 10 μM, less than about 15 μM, or less than about 30 μM. Inone embodiment, the cells are sensitive to a compound provided herein,e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, where the EC₅₀ of thecompound is between about 0.001 μM and about 30 μM, between about 0.01μM and about 30 μM, between about 0.1 μM and about 30 μM, between about1 μM and about 30 μM, between about 3 μM and about 30 μM, or betweenabout 10 μM and about 30 μM. In one embodiment, the cells are sensitiveto a compound provided herein, e.g., a compound of formula (I), or anenantiomer, a mixture of enantiomers or a mixture of diastereomersthereof, wherein the EC₅₀ of the compound is about 0.001 μM, about 0.005μM, about 0.01 μM, about 0.05 μM, about 0.1 μM, about 0.3 μM, about 0.5μM, about 0.7 μM, about 1 μM, about 3 μM, about 5 μM, about 10 μM, about15 μM, about 30 μM, or greater than 30 μM.

2. Treatment, Prevention, and/or Amelioration of Disorders

In one embodiment, provided herein is a method of treating, preventing,or ameliorating one or more symptoms of a disorder mediated by proteintranslation, comprising administering a compound provided herein, e.g.,a compound of formula (I), or an enantiomer, a mixture of enantiomers,or a mixture of two or more diastereomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, or apharmaceutical composition provided herein. In one embodiment, providedherein is a method of treating, preventing, or ameliorating one or moresymptoms of a disorder mediated by eIF4E, comprising administering acompound provided herein, e.g., a compound of formula (I), or anenantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, or a pharmaceutical composition providedherein. In one embodiment, the disorder is cancer, a proliferativedisorder, breast cancer, triple negative breast cancer, ER+breastcancer, ER− breast cancer, basal cell nevus syndrome (Gorlin syndrome),basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer,non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma,colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer,pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma,gastric cancer, gastroesophageal junction cancer, prostate cancer,cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantlecell lymphoma, diffuse large B-cell lymphoma, solid tumors that cannotbe removed by surgery, locally advanced solid tumors, metastatic solidtumors, leukemia, acute myeloid leukemia (AML), acute lymphoblasticleukemia (ALL), chronic myeloid leukemia (CML), or recurrent orrefractory tumors. In one embodiment, the disorder is basal cellcarcinoma associated with Gorlin syndrome.

In one embodiment, provided herein is a method for the treatment,prevention, or amelioration of one or more symptoms of a disorder, suchas cancer, a proliferative disorder, or a disorder mediated byangiogenesis, in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof. In one embodiment, the subject is ahuman. In one embodiment, the subject is a mammal. In one embodiment,the subject is a rodent, such as, e.g., mice or rats. In one embodiment,the subject is a primate. In one embodiment, the subject is a non-humanprimate, a farm animal such as cattle, a sport animal such as horses, ora pet such as dogs or cats.

In one embodiment, provided herein is use of a compound, e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof, or a pharmaceutical compositioncomprising the compound, in the manufacture of a medicament for thetreatment, prevention, or amelioration of a disorder provided herein. Inone embodiment, provided herein is a compound, e.g., a compound offormula (I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, or a pharmaceutical composition comprisingthe compound, for use in the treatment, prevention, or amelioration of adisorder provided herein. In one embodiment, the disorder is cancer. Inone embodiment, the disorder is a proliferative disorder. In oneembodiment, provided herein is use of a compound, e.g., a compound offormula (I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, or a pharmaceutical composition comprisingthe compound, in the manufacture of a medicament for the treatment ofcancer.

In one embodiment, the disorder that can be treated, prevented, orameliorated is a disorder, disease, or condition associated with eIF4Elevels in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof. In one embodiment, the disorderthat can be treated, prevented, or ameliorated is a disorder, disease,or condition associated with protein translation initiation in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein, e.g., a compound offormula (I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof. In one embodiment, the disorder that can betreated, prevented, or ameliorated is a disorder, disease, or conditionresponsive to the modulation of eIF4E levels in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of formula (I), or anenantiomer, a mixture of enantiomers or a mixture of diastereomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof. In one embodiment, the disorder that can be treated,prevented, or ameliorated is a disorder, disease, or condition mediatedby eIF4F complex in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof

In one embodiment, the disorder that can be treated, prevented, orameliorated is cancer or a proliferative disorder, including but notlimited to, breast cancer (e.g., triple negative breast cancer,ER+breast cancer, or ER− breast cancer), basal cell carcinoma, skincancer, lung cancer, small cell lung cancer, non-small cell lung cancer,brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovariancancer, liver cancer, pancreatic cancer (e.g., carcinoma, angiosarcoma,adenosarcoma), gastric cancer, gastroesophageal junction cancer,prostate cancer, cervical cancer, bladder cancer, head and neck cancer,lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma),solid tumors that cannot be removed by surgery, locally advanced solidtumors, metastatic solid tumors, leukemia (e.g., acute myeloid leukemia(AML), acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia(CML)), or recurrent or refractory tumors. In one embodiment, thedisorder that can be treated, prevented, or ameliorated includes, but isnot limited to, basal cell nevus syndrome (Gorlin syndrome). In oneembodiment, the disorder that can be treated, prevented, or amelioratedincludes, but is not limited to, basal cell carcinoma associated withGorlin syndrome.

In one embodiment, the compounds provided herein inhibit angiogenesisand are useful in the treatment of diseases or conditions mediated byangiogenesis. In one embodiment, the compounds provided herein areuseful for treating tumors, e.g., solid tumors, such as, e.g., colon,lung, pancreatic, ovarian, breast and glioma. In one embodiment, thecompounds provided herein are useful for treating macular degeneration,such as, e.g., wet age-related macular degeneration. In one embodiment,the compounds provided herein are useful for treatinginflammatory/immune diseases, such as, e.g., Crohn's disease,inflammatory bowel disease, Sjogren's syndrome, asthma, organ transplantrejection, systemic lupus erythmatoses, rheumatoid arthritis, psoriaticarthritis, psoriasis, and multiple sclerosis. In one embodiment, thecompounds provided herein are useful as a depilatory.

In one embodiment, the method provided herein comprises the step ofidentifying in a subject the presence of a certain type of cancer. Inone embodiment, the method provided herein comprises the step ofidentifying in a subject the presence of a type of cancer that issensitive to eIF4E modulation. In one embodiment, the method providedherein comprises the step of administering a compound provided herein,e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, to a subjecthaving a certain type of cancer.

In one embodiment, provided herein are methods of treating, preventing,or ameliorating cancer in the primary tumor, in the lymph nodes, and/orafter distant metastasis, comprising administering a compound providedherein, e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, to a subject inneed thereof. In one embodiment, provided herein are methods oftreating, preventing, or ameliorating cancer in the primary tumor,comprising administering a compound provided herein, e.g., a compound offormula (I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, to a subject in need thereof. In oneembodiment, provided herein are methods of preventing metastasiscomprising administering a compound provided herein, e.g., a compound offormula (I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, to a subject in need thereof. In oneembodiment, provided herein are methods of treating, preventing, orameliorating cancer in the lymph nodes, comprising administering acompound provided herein, e.g., a compound of formula (I), or anenantiomer, a mixture of enantiomers or a mixture of diastereomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof, to a subject in need thereof. In one embodiment,provided herein are methods of treating, preventing, or amelioratingcancer after distant metastasis, comprising administering a compoundprovided herein, e.g., a compound of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof,to a subject in need thereof

In one embodiment, provided herein are methods of treating, preventing,or ameliorating cancer in a subject having surgically resectable cancer,locally advanced cancer, regionally advanced cancer, and/or distantmetastatic cancer, comprising administering a compound provided herein,e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, to a subject inneed thereof. In one embodiment, provided herein are methods oftreating, preventing, or ameliorating cancer in a subject havingsurgically resectable cancer, comprising administering a compoundprovided herein, e.g., a compound of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof,to a subject in need thereof. In one embodiment, provided herein aremethods of treating, preventing, or ameliorating cancer in a subjecthaving locally advanced cancer, comprising administering a compoundprovided herein, e.g., a compound of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof,to a subject in need thereof. In one embodiment, provided herein aremethods of treating, preventing, or ameliorating cancer in a subjecthaving regionally advanced cancer, comprising administering a compoundprovided herein, e.g., a compound of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof,to a subject in need thereof. In one embodiment, provided herein aremethods of treating, preventing, or ameliorating cancer in a subjecthaving distant metastatic cancer, comprising administering a compoundprovided herein, e.g., a compound of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof,to a subject in need thereof

In one embodiment, provided herein are methods of treating, preventing,or ameliorating breast cancer comprising administering a compoundprovided herein, e.g., a compound of formula (I), or an enantiomer, amixture of enantiomers or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof,to a subject having breast cancer. In one embodiment, provided herein isa method of treating, preventing, or ameliorating triple negative breastcancer comprising administering a compound provided herein, e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof.

In one embodiment, provided herein are methods of treating, preventing,or ameliorating certain stages of breast cancer, including but notlimited to, Stage 0, Stage I, Stage IIA, Stage IIB, Stage IIIA, StageIIIB, Stage IIIC, and Stage IV, by administering a compound providedherein, e.g., a compound of formula (I), or an enantiomer, a mixture ofenantiomers or a mixture of diastereomers thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, to a subject inneed thereof. The staging of breast cancer may be defined according tomethods known in the art, for example, according to the guidelinesprovided by the American Joint Committee on Cancer (AJCC). In oneembodiment, the staging of breast cancer is designated and grouped basedon the TNM classification, i.e., a classification based on the status ofprimary tumor (e.g., TX, T0, T1s, T1, T2, T3, T4), regional lymph nodes(e.g., NX, N0, N1, N2, N3), and/or distant metastasis (e.g., MX, M0,M1), in a subject having breast cancer. See, e.g., Breast in: AmericanJoint Committee on Cancer: AJCC Cancer Staging Manual, 6th ed., NewYork, N.Y., Springer, 2002, 171-80.

In one embodiment, provided herein are methods for treating subjectshaving breast cancer, including, e.g., particular breast cancersubtypes, using a compound provided herein, e.g., a compound of formula(I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof. In one embodiment, the tumor is estrogenreceptor-negative, progesterone receptor-negative and HER2-negative. Inone embodiment, provided herein are methods comprising the step ofidentifying in a subject the presence of a particular type of breastcancer, including e.g., triple negative breast cancer, and the step ofadministering a compound provided herein, e.g., a compound of formula(I), or an enantiomer, a mixture of enantiomers or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, to the subject.

In one embodiment, the disorders, diseases, or conditions treatable witha compound provided herein, include, but are not limited to, (1)inflammatory or allergic diseases, including systemic anaphylaxis andhypersensitivity disorders, atopic dermatitis, urticaria, drugallergies, insect sting allergies, food allergies (including celiacdisease and the like), and mastocytosis; (2) inflammatory boweldiseases, including Crohn's disease, ulcerative colitis, ileitis, andenteritis; (3) vasculitis, and Behcet's syndrome; (4) psoriasis andinflammatory dermatoses, including dermatitis, eczema, atopicdermatitis, allergic contact dermatitis, urticaria, viral cutaneouspathologies including those derived from human papillomavirus, HIV orRLV infection, bacterial, flugal, and other parasital cutaneouspathologies, and cutaneous lupus erythematosus; (5) asthma andrespiratory allergic diseases, including allergic asthma, exerciseinduced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In one embodiment, the cancer treatable with the methods provided hereinincludes, but is not limited to, (1) leukemias, including, but notlimited to, acute leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, acute myelocytic leukemias such as myeloblastic,promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias andmyelodysplastic syndrome or a symptom thereof (such as anemia,thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractoryanemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts(RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronicmyelomonocytic leukemia (CMML), (2) chronic leukemias, including, butnot limited to, chronic myelocytic (granulocytic) leukemia, chroniclymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera;(4) lymphomas, including, but not limited to, Hodgkin's disease andnon-Hodgkin's disease; (5) multiple myelomas, including, but not limitedto, smoldering multiple myeloma, nonsecretory myeloma, osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonalgammopathy of undetermined significance; (8) benign monoclonalgammopathy; (9) heavy chain disease; (10) bone and connective tissuesarcomas, including, but not limited to, bone sarcoma, osteosarcoma,chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11)brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, oligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; (12) breast cancer,including, but not limited to, adenocarcinoma, lobular (small cell)carcinoma, intraductal carcinoma, medullary breast cancer, mucinousbreast cancer, tubular breast cancer, papillary breast cancer, primarycancers, Paget's disease, and inflammatory breast cancer; (13) adrenalcancer, including, but not limited to, pheochromocytom andadrenocortical carcinoma; (14) thyroid cancer, including, but notlimited to, papillary or follicular thyroid cancer, medullary thyroidcancer, and anaplastic thyroid cancer; (15) pancreatic cancer,including, but not limited to, insulinoma, gastrinoma, glucagonoma,vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;(16) pituitary cancer, including, but limited to, Cushing's disease,prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eyecancer, including, but not limited, to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; (18) vaginal cancer, including, but not limited to,squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvarcancer, including, but not limited to, squamous cell carcinoma,melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget'sdisease; (20) cervical cancers, including, but not limited to, squamouscell carcinoma, and adenocarcinoma; (21) uterine cancer, including, butnot limited to, endometrial carcinoma and uterine sarcoma; (22) ovariancancer, including, but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; (23) esophagealcancer, including, but not limited to, squamous cancer, adenocarcinoma,adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamouscarcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oatcell (small cell) carcinoma; (24) stomach cancer, including, but notlimited to, adenocarcinoma, fungating (polypoid), ulcerating,superficial spreading, diffusely spreading, malignant lymphoma,liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26)rectal cancer; (27) liver cancer, including, but not limited to,hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer,including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas,including, but not limited to, pappillary, nodular, and diffuse; (30)lung cancer, including, but not limited to, non-small cell lung cancer,squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma,large-cell carcinoma, and small-cell lung cancer; (31) testicularcancer, including, but not limited to, germinal tumor, seminoma,anaplastic, classic (typical), spermatocytic, nonseminoma, embryonalcarcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor);(32) prostate cancer, including, but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oralcancer, including, but not limited to, squamous cell carcinoma; (35)basal cancer; (36) salivary gland cancer, including, but not limited to,adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma;(37) pharynx cancer, including, but not limited to, squamous cell cancerand verrucous; (38) skin cancer, including, but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma, andacral lentiginous melanoma; (39) kidney cancer, including, but notlimited to, renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer);(40) Wilms' tumor; (41) bladder cancer, including, but not limited to,transitional cell carcinoma, squamous cell cancer, adenocarcinoma, andcarcinosarcoma; and other cancer, including, not limited to,myxosarcoma, osteogenic sarcoma, endotheliosarcoma,lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma,epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweatgland carcinoma, sebaceous gland carcinoma, papillary carcinoma, andpapillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed.,J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, InformedDecisions: The Complete Book of Cancer Diagnosis, Treatment, andRecovery, Viking Penguin, Penguin Books U.S.A., Inc., United States ofAmerica).

Particular embodiments provide treating a subject having cancer usingone or more of the methods provided herein, together with surgery.Particular embodiments provide treating a subject having cancer usingone or more of the methods provided herein, together with chemotherapy.Particular embodiments provide treating a subject having cancer usingone or more of the methods provided herein, together with immunotherapy.Particular embodiments provide treating a subject having cancer usingone or more of the methods provided herein, together with targetedtherapy. Particular embodiments provide treating a subject having cancerusing one or more of the methods provided herein, together withradiation therapy. Particular embodiments provide treating a subjecthaving cancer using one or more of the methods provided herein, togetherwith two or more of the treatments selected from surgery, chemotherapy,immunotherapy, targeted therapy, and radiation therapy.

In certain embodiments, the subject to be treated with one of themethods provided herein has not been treated with anticancer therapyprior to the administration of a compound provided herein. In certainembodiments, the subject to be treated with one of the methods providedherein has been treated with one or more anticancer therapies prior tothe administration of a compound provided herein. In certainembodiments, the subject to be treated with one of the methods providedherein has been treated with a cancer therapeutic agent, as describedherein. In certain embodiments, the subject to be treated with one ofthe methods provided herein has developed drug resistance to anticancertherapy. In certain embodiments, the subject to be treated with themethods provided herein has a relapsed cancer. In certain embodiments,the subject to be treated with the methods provided herein has arefractory cancer. In certain embodiments, the subject to be treatedwith the methods provided herein has a metastatic cancer.

In one embodiment, provided herein are methods for treating a subjecthaving a cancer, comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof; wherein the cancer is resistant toconventional therapy (e.g., resistant to other anticancer drugs). In oneembodiment, the cancer treated by a compound provided herein, e.g., acompound of formula (I), is resistant to one or more anticancer drug(s),including, but not limited to, vincristine, taxol, cytarabine, and/ordoxorubicin. In one embodiment, the cancer is resistant to a therapeuticagent described herein (e.g., Section E.5, infra). In one embodiment,the cancer is vincristine-resistant. In one embodiment, the cancer istaxol-resistant. In one embodiment, the cancer is cytarabine-resistant.In one embodiment, the cancer is doxorubicin-resistant. In oneembodiment, the cancer is resistant to a therapeutic agent thatmodulates microtubule formation. In one embodiment, the cancer isresistant to a therapeutic agent that is associated with p-glycoproteinmediated multidrug resistance.

In one embodiment, the methods provided herein encompass treating asubject regardless of patient's age, although some diseases or disordersare more common in certain age groups. Further provided herein is amethod for treating a subject who has undergone surgery in an attempt totreat the disease or condition at issue. Further provided herein is amethod for treating a subject who has not undergone surgery as anattempt to treat the disease or condition at issue. Because the subjectswith cancer have heterogeneous clinical manifestations and varyingclinical outcomes, the treatment given to a particular subject may vary,depending on his/her prognosis. The skilled clinician will be able toreadily determine without undue experimentation, specific secondaryagents, types of surgery, and types of non-drug based standard therapythat can be effectively used to treat an individual subject with cancer.

In each embodiment provided herein, the method may further comprise oneor more diagnostic steps, to determine, e.g., the type of cancer, thepresence of particular cell types, and/or the staging of the disease ina subject.

In each embodiment provided herein, the method may further comprise adisease evaluation step after the compound or pharmaceutical compositionhas been administered to the subject, to determine, e.g., changes in oneor more molecular markers as described herein elsewhere, changes intumor size and location, and/or other benchmarks used by those skilledin the art to determine the prognosis of cancer in a subject.

3. Biomarkers

In certain embodiments, appropriate biomarkers may be used to determineor predict the effect of the methods provided herein on the diseasestate and to provide guidance as to the dosing schedule and dosageamount. In particular embodiments, the greater benefit is an overallsurvival benefit. In particular embodiments, the greater benefit istumor stasis and remission. In particular embodiments, the greaterbenefit is prevention of tumor recurrence. In one embodiment, providedherein is a method for determining whether a patient diagnosed withcancer has an increased probability of obtaining a greater benefit fromtreatment with a compound provided herein by assessing the level ofeIF4E in the tumor biopsy samples obtained from the patient. In oneembodiment, provided herein is a method for determining whether apatient diagnosed with cancer has an increased probability of obtaininga greater benefit from treatment with a compound provided herein byassessing the sensitivity of cancer cells obtained from the patient tothe downregulation of protein translation initiation. In one embodiment,the method comprises assessing the activity of a compound providedherein in tumor biopsy samples in vitro. In one embodiment, the methodcomprises assessing the levels of one or more growth factors and/orcytokines that are important in cancer progression and weaklytranslated. In one embodiment, the growth factor markers and cytokinemarkers include, but are not limited to, VEFG, FGF, IL-1, and TGF-β. Inone embodiment, provided herein is a method for determining the responseof a patient to the treatment of a compound provided herein, byassessing one or more of the molecular biomarkers described herein. Inone embodiment, the dosage of a compound used in treating a patient isadjusted based on the result of biomarker responses in the particularpatient after initial treatment with the compound.

4. Administration of Compounds

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided is administration of the compounds orpharmaceutical compositions provided herein in a depot formulation, inwhich the active ingredient is released over a predefined time period.In one embodiment, the compound or composition is administered orally.In another embodiment, the compound or composition is administeredparenterally. In yet another embodiment, the compound or composition isadministered intravenously.

Certain methods herein provide the administration of a compound providedherein by intravenous (IV), subcutaneous (SC) or oral routesadministration. Certain embodiments herein provide co-administration ofa compound provided herein with one or more additional active agents toprovide a synergistic therapeutic effect in subjects in need thereof.The co-administered agent(s) may be a cancer therapeutic agent, asdescribed herein. In certain embodiments, the co-administered agent(s)may be dosed, e.g., orally or by injection (e.g., IV or SC).

Certain embodiments herein provide methods for treating disorders ofabnormal cell proliferation comprising administering a compound providedherein using, e.g., IV, SC and/or oral administration methods. Incertain embodiments, treatment cycles comprise multiple dosesadministered to a subject in need thereof over multiple days (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days),optionally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days). Suitabledosage amounts for the methods provided herein include, e.g.,therapeutically effective amounts and prophylactically effectiveamounts. For example, in certain embodiments, the amount of a compoundprovided herein administered in the methods provided herein may range,e.g., between about 10 mg/day and about 2,000 mg/day, between about 20mg/day and about 1,000 mg/day, between about 50 mg/day and about 1,000mg/day, between about 100 mg/day and about 1,000 mg/day, between about100 mg/day and about 500 mg/day, between about 100 mg/day and about 200mg/day, or between about 200 mg/day and about 500 mg/day. In certainembodiments, particular dosages are, e.g., up to about 10 mg/day, up toabout 20 mg/day, up to about 40 mg/day, up to about 60 mg/day, up toabout 80 mg/day, up to about 100 mg/day, up to about 120 mg/day, up toabout 140 mg/day, up to about 150 mg/day, up to about 160 mg/day, up toabout 180 mg/day, up to about 200 mg/day, up to about 220 mg/day, up toabout 240 mg/day, up to about 250 mg/day, up to about 260 mg/day, up toabout 280 mg/day, up to about 300 mg/day, up to about 320 mg/day, up toabout 350 mg/day, up to about 400 mg/day, up to about 450 mg/day, up toabout 500 mg/day, up to about 750 mg/day, or up to about 1000 mg/day. Incertain embodiments, particular dosages are, e.g., about 10 mg/day,about 20 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day,about 120 mg/day, about 150 mg/day, about 200 mg/day, about 250 mg/day,about 300 mg/day, about 350 mg/day, about 400 mg/day, about 450 mg/day,about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day,about 900 mg/day, about 1,000 mg/day, about 1,200 mg/day, or about 1,500mg/day.

In one embodiment, the amount of a compound provided herein in thepharmaceutical composition or dosage form provided herein may range,e.g., between about 5 mg and about 2,000 mg, between about 10 mg andabout 2,000 mg, between about 20 mg and about 2,000 mg, between about 50mg and about 1,000 mg, between about 100 mg and about 500 mg, betweenabout 150 mg and about 500 mg, or between about 150 mg and about 250 mg.In certain embodiments, the amount of a compound provided herein in thepharmaceutical composition or dosage form provided herein is, e.g.,about 10 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, orabout 1,500 mg. In certain embodiments, the amount of a compoundprovided herein in the pharmaceutical composition or dosage formprovided herein is, e.g., up to about 10 mg, up to about 20 mg, up toabout 50 mg, up to about 75 mg, up to about 100 mg, up to about 120 mg,up to about 150 mg, up to about 200 mg, up to about 250 mg, up to about300 mg, up to about 350 mg, up to about 400 mg, up to about 450 mg, upto about 500 mg, up to about 600 mg, up to about 700 mg, up to about 800mg, up to about 900 mg, up to about 1,000 mg, up to about 1,200 mg, orup to about 1,500 mg.

In one embodiment, the compound or composition can be delivered as asingle dose such as, e.g., a single bolus injection, or oral tablets orpills; or over time such as, e.g., continuous infusion over time ordivided bolus doses over time. In one embodiment, the compound orcomposition can be administered repetitively if necessary, for example,until the patient experiences stable disease or regression, or until thepatient experiences disease progression or unacceptable toxicity. Forexample, stable disease for solid tumors generally means that theperpendicular diameter of measurable lesions has not increased by 25% ormore from the last measurement.

See, e.g., Response Evaluation Criteria in Solid Tumors (RECIST)Guidelines, Journal of the National Cancer Institute 92(3): 205-216(2000). Stable disease or lack thereof is determined by methods known inthe art such as evaluation of patient's symptoms, physical examination,visualization of the tumor that has been imaged using X-ray, CAT, PET,or MRI scan and other commonly accepted evaluation modalities.

In one embodiment, the compound or composition can be administered oncedaily (QD), or divided into multiple daily doses such as twice daily(BID), three times daily (TID), and four times daily (QID). In oneembodiment, the administration can be continuous (i.e., daily forconsecutive days or every day), intermittent, e.g., in cycles (i.e.,including days, weeks, or months of rest when no drug is administered).In one embodiment, the compound or composition is administered daily,for example, once or more than once each day for a period of time. Inone embodiment, the compound or composition is administered daily for anuninterrupted period of at least 7 days, in some embodiments, up to 52weeks. In one embodiment, the compound or composition is administeredintermittently, i.e., stopping and starting at either regular orirregular intervals. In one embodiment, the compound or composition isadministered for one to six days per week. In one embodiment, thecompound or composition is administered in cycles (e.g., dailyadministration for two to eight consecutive weeks, then a rest periodwith no administration for up to one week). In one embodiment, thecompound or composition is administered on alternate days. In oneembodiment, the compound or composition is administered in cycles (e.g.,administered daily or continuously for a certain period interrupted witha rest period).

In one embodiment, the frequency of administration ranges from aboutdaily to about monthly. In certain embodiments, the compound orcomposition is administered once a day, twice a day, three times a day,four times a day, once every other day, twice a week, once every week,once every two weeks, once every three weeks, or once every four weeks.

In one embodiment, the compound or composition is administered dailyfrom one day to six months, from one week to three months, from one weekto four weeks, from one week to three weeks, or from one week to twoweeks. In certain embodiments, the compound or composition isadministered daily for one week, two weeks, three weeks, or four weeks.In one embodiment, the compound or composition is administered once perday for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about6 weeks, about 9 weeks, about 12 weeks, about 15 weeks, about 18 weeks,about 21 weeks, or about 26 weeks. In certain embodiments, the compoundor composition is administered intermittently. In certain embodiments,the compound or composition is administered continuously. In certainembodiments, the compound or composition is administered to a subject incycles. Cycling therapy involves the administration of an active agentfor a period of time, followed by a rest for a period of time, andrepeating this sequential administration. Cycling therapy can reduce thedevelopment of resistance, avoid or reduce the side effects, and/orimproves the efficacy of the treatment.

It is understood that the duration of the treatment may vary with theage, weight, and condition of the subject being treated, and may bedetermined empirically using known testing protocols or according to theprofessional judgment of the person providing or supervising thetreatment. The skilled clinician will be able to readily determine,without undue experimentation, an effective drug dose and treatmentduration, for treating an individual subject having a particular type ofcancer.

5. Co-Administered Therapeutic Agents

In one embodiment, the method provided herein for treating, preventing,or ameliorating a disorder provided herein comprise co-administering acompound provided herein, e.g., a compound of formula (I), or anenantiomer, a mixture of enantiomers or a mixture of diastereomersthereof, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof, with one or more therapeutic agents, such as, e.g.,cancer therapeutic agents, to yield a synergistic therapeutic effect. Inone embodiment, the disorder being treated, prevented, or ameliorated iscancer. In one embodiment, the co-administered therapeutic agentsinclude, but are not limited to, e.g., cytotoxic agents,anti-metabolites, antifolates, HDAC inhibitors such as MGCD0103 (a.k.a.N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide),DNA intercalating agents, DNA cross-linking agents, DNA alkylatingagents, DNA cleaving agents, topoisomerase inhibitors, CDK inhibitors,JAK inhibitors, anti-angiogenic agents, Bcr-Abl inhibitors, HER2inhibitors, EGFR inhibitors, VEGFR inhibitors, PDGFR inhibitors, HGFRinhibitors, IGFR inhibitors, c-Kit inhibitors, Ras pathway inhibitors,PI3K inhibitors, multi-targeted kinase inhibitors, mTOR inhibitors,antiestrogens, anti-androgens, aromatase inhibitors, somatostatinanalogs, ER modulators, anti-tubulin agents, vinca alkaloids, taxanes,HSP inhibitors, Smoothened antagonists, telomerase inhibitors, COX-2inhibitors, anti-metastatic agents, immunosuppressants, biologics suchas antibodies, and hormonal therapies. The co-administered agent may bedosed, e.g., orally or by injection. In one embodiment, each methodprovided herein may independently, further comprise the step ofadministering a second therapeutic agent, including, e.g., an anticanceragent.

In one embodiment, one or more therapeutic agent is/are an anticanceragent to be coadministered with a compound provided herein e.g., acompound of formula (I), or an enantiomer, a mixture of enantiomers or amixture of diastereomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof. In one embodiment, the anticanceragent is an antimetabolite, including, but not limited to, 5-fluorouracil, methotrexate, cytarabine, high dose cytarabine, and fludarabine.In one embodiment, the anticancer agent is an antimicrotubule agent,including, but not limited to, vinca alkaloids (e.g., vincristine andvinblastine) and taxanes (e.g., paclitaxel and docetaxel). In oneembodiment, the anticancer agent is an alkylating agent, including, butnot limited to, cyclophosphamide, melphalan, carmustine, andnitrosoureas (e.g., hydroxyurea and bischloroethylnitrosurea). In oneembodiment, the anticancer agent is a platinum agent, including, but notlimited to, cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216),and CI-973. In one embodiment, the anticancer agent is an anthracycline,including, but not limited to, doxrubicin and daunorubicin. In oneembodiment, the anticancer agent is an antitumor antibiotic, including,but not limited to, mitomycin, idarubicin, adriamycin, and daunomycin(also known as daunorubicin). In one embodiment, the anticancer agent isa topoisomerase inhibitor, e.g., etoposide and camptothecins. In oneembodiment, the anticancer agent is selected from the group consistingof adriamycin, busulfan, cytarabine, cyclophosphamide, dexamethasone,fludarabine, fluorouracil, hydroxyurea, interferons, oblimersen,platinum derivatives, taxol, topotecan, and vincristine.

In one embodiment, the route of the administration of the compoundprovided herein is independent of the route of the administration of asecond therapy. In one embodiment, the compound provided herein isadministered orally. In another embodiment, the compound provided hereinis administered intravenously. In accordance with these embodiments,i.e., administering the compound provided herein orally orintravenously, the second therapy can be administered orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form. In one embodiment, the compound provided herein and asecond therapy are administered by the same mode of administration,e.g., orally or intravenously. In another embodiment, the compoundprovided herein is administered by one mode of administration, e.g.,orally, whereas the second agent (e.g., an anticancer agent) isadministered by another mode of administration, e.g., intravenously. Inanother embodiment, the compound provided herein is administered by onemode of administration, e.g., intravenously, whereas the second agent(e.g., an anticancer agent) is administered by another mode ofadministration, e.g., orally.

Suitable other therapeutic agents can also include, but are not limitedto, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporine; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat; and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

In one embodiment, other therapies or anticancer agents that may be usedin combination with the compound provided herein include surgery,radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes), endocrine therapy, biologic response modifiers(e.g., interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, agents to attenuate any adverse effects(e.g., antiemetics), and other approved chemotherapeutic drugs,including, but not limited to, alkylating drugs (mechlorethamine,chlorambucil, cyclophosphamide, melphalan, and ifosfamide),antimetabolites (cytarabine, high dose cytarabine, and methotrexate),purine antagonists and pyrimidine antagonists (6-mercaptopurine,5-fluorouracil, cytarabine, and gemcitabine), spindle poisons(vinblastine, vincristine, vinorelbine, and paclitaxel),podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics(daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas(carmustine and lomustine), inorganic ions (cisplatin and carboplatin),enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide,and megestrol), imatinib, adriamycin, dexamethasone, andcyclophosphamide. For additional available cancer therapies, see, e.g,http://www.nci.nih.gov/; for a list of FDA approved oncology drugs, see,e.g., http://www.fda.gov/, The Merck Manual, 18th Ed. 2006, and PDR:Physician Desk Reference 2010, 64th Ed. 2009; the contents of each ofwhich are hereby incorporated by reference in their entireties.

EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

A. Synthesis of Compounds

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Aldrich in Sure-Seal bottles andused as received. All solvents may be purified using standard methodsknown to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. In one embodiment, the reactionflasks were fitted with rubber septa for introduction of substrates andreagents via syringe. In one embodiment, analytical thin layerchromatography (TLC) was performed using glass-backed silica gelpre-coated plates (Whatman MK6F Silica Gel 60 Å, 2.5×7.6 cm, TLC plates)and eluted with appropriate solvent ratios (v/v). In one embodiment,reactions were assayed by TLC, HPLC, or LCMS, and terminated as judgedby the consumption of starting material. In one embodiment,visualization of the TLC plates was done with UV light (254 wavelength)or with an appropriate TLC visualizing solvent, such as basic aqueousKMnO₄ solution activated with heat. In one embodiment, flash columnchromatography (See, e.g., Still et al., J. Org. Chem., 43: 2923 (1978))was performed using silica gel 60 (Whatman Silica Gel 60 Å 70-230 MeshASTM) or various MPLC systems.

The compound structures in the examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,mass spectroscopy, elemental microanalysis, and melting point. In oneembodiment, proton magnetic resonance (¹H-NMR) spectra were determinedusing a NMR spectrometer operating at a certain field strength. Chemicalshifts are reported in parts per million (ppm, δ) downfield from aninternal standard, such as TMS. Alternatively, ¹H-NMR spectra werereferenced to signals from residual protons in deuterated solvents asfollows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm; C₆D₆=7.16 ppm; CD₃OD=3.30ppm. Peak multiplicities are designated as follows: s, singlet; d,doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets;q, quartet; br, broadened; and m, multiplet. Coupling constants aregiven in Hertz (Hz). In one embodiment, mass spectra (MS) data wereobtained using a mass spectrometer with APCI or ESI ionization.

Example 1 Compound 1:N-[3,5-Bis(trifluoromethyl)phenyl]-2,4,6-triisopropyl-benzenesulfonamide

Method A. 2,4,6-Triisopropyl-benzenesulfonyl chloride (0.210 g, 0.693mmol) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine(0.159 g, 0.693 mmol) in dry pyridine (1 mL). After stirring at roomtemperature for 1 day, the reaction was concentrated under vacuum. Tothis was added ethyl acetate (30 mL), and the mixture was washed withdilute HCl (2×30 mL) followed by saturated NaHCO₃ (2×30 mL) then brine(saturated NaCl, 2×30 mL). After drying the organic layer over MgSO₄,the mixture was concentrated under vacuum. The crude compound waspurified by silica gel chromatography using hexanes/ethyl acetate (10:1)to afford the title compound (0.046 g. 13% yield). ES-MS negative Q1(m/z) 494.7. ¹H NMR (CDCl₃) 7.55 (s, 1H), 7.31 (s, 2H), 7.18 (s, 2H),6.98 (s, 1H), 4.10 (m, 2H), 2.90 (m, 1H), 1.23 (m, 18H).

Compound 1:N-[3,5-Bis(trifluoromethyl)phenyl]-2,4,6-triisopropyl-benzenesulfonamide

Method B. 2,4,6-Triisopropyl-benzenesulfonyl chloride (5.00 g, 16.5mmol) was added to a solution of 3,5-bis(trifluoromethyl)aniline (3.79g, 16.5 mmol) in dry pyridine (4 mL). The reaction was capped andstirred at room temperature for 2 days then concentrated under vacuum.To this was added diethyl ether (100 mL), and the mixture was washedwith 0.1 N HCl (2×30 mL) followed by saturated NaHCO₃ (2×30 mL) thensaturated NaCl (2×30 mL). After drying the organic layer over MgSO₄, themixture was concentrated under vacuum. The crude compound was passedthrough a plug of silica gel, eluted with ether, and concentrated. Theresulting solid was triturated with hexanes to afford the title compound(3.72 g. 43% yield). ES-MS negative Q1 (m/z) 494.7. ¹H NMR (CDCl₃) 7.55(s, 1H), 7.32 (s, 2H), 7.18 (s, 2H), 6.99 (s, 1H), 4.09 (m, 2H), 2.90(m, 1H), 1.23 (m, 18H).

Example 2 Compound 2:N-[2-Methyl-3,5-bis(trifluoromethyl)phenyl]-2,4,6-triisopropyl-benzenesulfonamide

Method A. 2,4,6-Triisopropyl-benzenesulfonyl chloride (0.150 g, 0.495mmol) was added to a solution of2-methyl-3,5-bis-trifluoromethyl-phenylamine (0.120 g, 0.495 mmol) indry pyridine (1 mL). After stirring at room temperature for 1 day, thereaction was concentrated under vacuum. To this was added ethyl acetate(30 mL), and the mixture was washed with dilute HCl (2×30 mL) followedby saturated NaHCO₃ (2×30 mL) then brine (saturated NaCl, 2×30 mL).After drying the organic layer over MgSO₄, the mixture was concentratedunder vacuum. The crude compound was purified by silica gelchromatography using hexanes/ethyl acetate (10:1) to afford the titlecompound (0.050 g. 20% yield). ES-MS negative Q1 (m/z) 508.5. ¹H NMR(CDCl₃) 7.67 (s, 1H), 7.19 (s, 2H), 7.18 (s, 1H), 6.46 (s, 1H), 3.97 (m,2H), 2.92 (m, 1H), 2.42 (s, 3H), 1.25 (d, 6H), 1.18 (d, 12H).

Compound 2:N-[2-Methyl-3,5-bis(trifluoromethyl)phenyl]-2,4,6-triisopropyl-benzenesulfonamide

Method B. 2,4,6-Triisopropyl-benzenesulfonyl chloride (2.49 g, 8.23mmol) was added to a solution of2-methyl-3,5-bis(trifluoromethyl)aniline (2.00 g, 8.23 mmol) and drypyridine (3 mL) in a 20 mL scintillation vial. The reaction was cappedand stirred at room temperature for 1 day then stirred at 30° C. for 1day. The reaction was then concentrated under vacuum. To this was addeddiethyl ether (125 mL) and the mixture was washed with 0.1 N HCl (3×30mL) followed by 0.1 N NaOH (2×30 mL) then saturated NaCl (2×30 mL).After drying the organic layer over MgSO₄, the solution was filtered andconcentrated under vacuum. The crude compound was triturated withhexanes (3×10 mL) then dried under vacuum to afford the title compound(1.68 g. 40% yield). ES-MS negative Q1 (m/z) 508.5. LCMS (M+Na) 532. ¹HNMR (CDCl₃) 7.67 (s, 1H), 7.19 (s, 2H), 7.18 (s, 1H), 6.50 (s, 1H), 3.98(m, 2H), 2.91 (m, 1H), 2.42 (s, 3H), 1.25 (d, 6H), 1.18 (d, 12H).

Example 3 Compound 3:N-[2-Chloro-3,5-bis(trifluoromethyl)phenyl]-2,4,6-triisopropyl-benzenesulfonamide

Method A. 2,4,6-Triisopropyl-benzenesulfonyl chloride (0.520 g, 1.97mmol) was added to a solution of2-chloro-3,5-bis-trifluoromethyl-phenylamine (0.597 g, 1.97 mmol) in drypyridine (4 mL). After stirring under nitrogren at 78° C. for 1 day, thereaction was concentrated under vacuum. To this was added ethyl acetate(90 mL), and the mixture was washed with dilute HCl (2×60 mL) followedby saturated NaHCO₃ (2×60 mL) then brine (saturated NaCl, 2×60 mL).After drying the organic layer over MgSO₄, the mixture was concentratedunder vacuum. The crude compound was purified by silica gelchromatography using hexanes/ethyl acetate (10:1) and recrystallizedfrom hexanes/ether (2:1) to afford the title compound (0.175 g. 18%yield). ES-MS negative Q1 (m/z) 528.9. ¹H NMR (CDCl₃) 7.64 (s, 1H), 7.59(s, 1H), 7.45 (bs, 1H), 7.19 (s, 2H), 4.10 (m, 2H), 2.90 (m, 1H), 1.24(m, 18H).

Compound 3:N-[2-Chloro-3,5-bis(trifluoromethyl)phenyl]-2,4,6-triisopropyl-benzenesulfonamide

Method B. 2,4,6-Triisopropyl-benzenesulfonyl chloride (2.49 g, 8.23mmol) was added to a solution of2-chloro-3,5-bis(trifluoromethyl)aniline (2.17 g, 8.23 mmol) and drypyridine (3 mL) in a 20 mL scintillation vial. The reaction was cappedand stirred at room temperature for 1 day then stirred at 30° C. for 1day. The reaction was then concentrated under vacuum. To this was addeddiethyl ether (125 mL) and the mixture was washed with 0.1 N HCl (3×30mL) followed by 0.1 N NaOH (2×30 mL) then saturated NaCl (2×30 mL).After drying the organic layer over MgSO₄, the solution was filtered andconcentrated under vacuum. The crude compound was triturated withhexanes (3×10 mL) then dried under vacuum to afford the title compound(1.26 g. 29% yield). ES-MS negative Q1 (m/z) 528.9. ¹H NMR (CDCl₃) 7.64(s, 1H), 7.59 (s, 1H), 7.45 (bs, 1H), 7.19 (s, 2H), 4.10 (m, 2H), 2.90(m, 1H), 1.24 (m, 18H).

Example 4 Compound 4:3,5-Bis(trifluoromethyl)-N-(2,4,6-triisopropylphenyl)benzenesulfonamide

3,5-Bis(trifluoromethyl)benzenesulfonyl chloride (0.037 g, 0.12 mmol)was added to a solution of 2,4,6-triisopropylaniline (0.025 g, 0.11mmol) in dry pyridine (1 mL). After stirring at room temperature for 1day, the reaction was concentrated under vacuum. To this was added ethylacetate (30 mL), and the mixture was washed with 0.1 N HCl (2×20 mL)followed by saturated NaHCO₃ (2×20 mL) then saturated NaCl (2×20 mL).After drying the organic layer over MgSO₄, the mixture was concentratedunder vacuum. The crude compound was purified by silica gelchromatography using hexanes/ethyl acetate (4:1) to afford the titlecompound (0.040 g. 71% yield). ES-MS negative Q1 (m/z) 494.6. ¹H NMR(CDCl₃) 8.14 (s, 2H), 8.05 (s, 1H), 6.96 (s, 2H), 6.05 (s, 1H), 2.97 (m,2H), 2.88 (m, 1H), 1.23 (d, 6H), 0.98 (d, 12H).

Example 5 Compound 5:N-[2-Bromo-3,5-bis(trifluoromethyl)phenyl]-2,4,6-triisopropyl-benzenesulfonamide

2,4,6-Triisopropyl-benzenesulfonyl chloride (0.491 g, 1.59 mmol) wasadded to a solution of 2-bromo-3,5-bis(trifluoromethyl)aniline (0.483 g,1.59 mmol) in dry pyridine (1 mL). The reaction was capped and stirredat room temperature for 1 day then stirred at 30° C. for 1 day. Thereaction was then concentrated under vacuum. To this was added diethylether (100 mL) and the mixture was washed with 0.1 N HCl (3×30 mL)followed by 0.1 N NaOH (2×30 mL) then saturated NaCl (2×30 mL). Afterdrying the organic layer over MgSO₄, the solution was filtered andconcentrated under vacuum. The crude compound was purified by silica gelchromatography using hexanes/ethyl acetate (10:1) to afford the titlecompound (0.036 g, 4% yield). LCMS (M+Na) 597.

Example 6 Compound 6:N-[3,5-Bis(trifluoromethyl)phenyl]-4-tert-butyl-2,6-dimethyl-benzenesulfonamide

4-Tert-butyl-2,6-dimethyl-benzenesulfonyl chloride (0.100 g, 0.383 mmol)was added to a solution of 3,5-bis(trifluoromethyl)aniline (0.089 g,0.387 mmol) in dry pyridine (1 mL). The reaction was capped and stirredat room temperature for 1 day then stirred at 30° C. for 1 day. Thereaction was then concentrated under vacuum. To this was added diethylether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL)followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). Afterdrying the organic layer over MgSO₄, the solution was filtered andconcentrated under vacuum. The crude compound was triturated withhexanes (2×10 mL) to afford the title compound (0.040 g, 23% yield).LCMS (M+Na) 476.

Example 7 Compound 7:2,6-Diethyl-N-[2-methyl-3,5-bis(trifluoromethyl)phenyl]benzenesulfonamide

2,6-Diethylbenzenesulfonyl chloride (0.100 g, 0.430 mmol) was added to asolution of 2-methyl-3,5-bis(trifluoromethyl)aniline (0.106 g, 0.434mmol) in dry pyridine (1 mL). The reaction was capped and stirred atroom temperature for 1 day then stirred at 30° C. for 1 day. Thereaction was then concentrated under vacuum. To this was added diethylether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL)followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). Afterdrying the organic layer over MgSO₄, the solution was filtered andconcentrated under vacuum. The crude compound was purified by silica gelchromatography using hexanes/ethyl acetate (4:1) to afford the titlecompound (0.080 g, 42% yield). LCMS (M+Na) 461.

Example 8 Compound 8:N-[3,5-Bis(trifluoromethyl)phenyl]-2,6-diethyl-benzene sulfonamide

2,6-Diethylbenzenesulfonyl chloride (0.100 g, 0.430 mmol) was added to asolution of 3,5-bis(trifluoromethyl)aniline (0.099 g, 0.434 mmol) in drypyridine (1 mL). The reaction was capped and stirred at room temperaturefor 1 day then stirred at 30° C. for 1 day. The reaction was thenconcentrated under vacuum. To this was added diethyl ether (60 mL) andthe mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH(2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layerover MgSO₄, the solution was filtered and concentrated under vacuum. Thecrude compound was triturated with hexanes (2×10 mL) to afford the titlecompound (0.037 g, 20% yield). LCMS (M+Na) 447.

Example 9 Compound 9:4-Tert-butyl-2,6-dimethyl-N-[2-methyl-3,5-bis(trifluoromethyl)phenyl]benzenesulfonamide

4-Tert-butyl-2,6-dimethyl-benzenesulfonyl chloride (0.100 g, 0.383 mmol)was added to a solution of 2-methyl-3,5-bis(trifluoromethyl)aniline(0.094 g, 0.387 mmol) in dry pyridine (1 mL). The reaction was cappedand stirred at room temperature for 1 day then stirred at 30° C. for 1day. The reaction was then concentrated under vacuum. To this was addeddiethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL).After drying the organic layer over MgSO₄, the solution was filtered andconcentrated under vacuum. The crude compound was triturated withhexanes (3×10 mL) to afford the title compound (0.051 g, 28% yield).LCMS (M+Na) 490.

Example 10 Compound 10:4-Tert-butyl-N-[2-chloro-3,5-bis(trifluoromethyl)phenyl]-2,6-dimethyl-benzenesulfonamide

4-Tert-butyl-2,6-dimethyl-benzenesulfonyl chloride (0.100 g, 0.383 mmol)was added to a solution of 2-chloro-3,5-bis(trifluoromethyl)aniline(0.101 g, 0.387 mmol) in dry pyridine (1 mL). The reaction was cappedand stirred at room temperature for 1 day then stirred at 30° C. for 1day. The reaction was then concentrated under vacuum. To this was addeddiethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL).After drying the organic layer over MgSO₄, the solution was filtered andconcentrated under vacuum. The crude compound was triturated withhexanes (2×10 mL) to afford the title compound (0.027 g, 14% yield).LCMS (M+Na) 510.

B. Determination of IC₅₀ in Cell-Based Assays

In one embodiment, the IC₅₀s of the compounds provided herein weredetermined in cell-based assays using adherent cells. In one embodiment,the activity of the compounds provided herein were determined in acell-based assay using the triple negative breast cancer cell lineMDA-MB-468. In one embodiment, the activity of the compounds providedherein were determined in a cell-based assay using the triple negativebreast cancer cell line MDA-MB-231. In one embodiment, the activity ofthe compounds provided herein were determined in a cell-based assayusing the triple negative breast cancer cell line 4T1.

In one embodiment, the cell-based assay may be carried out as providedherein. On day 0, cells were seeded at 20,000 cells per well in 100 μLof media into individual wells of a 96-well tissue culture plate. Thenext day, compounds were diluted to twice the desired finalconcentration and added in 100 μL of media for a final volume of 200 μL.Standard solutions for each compound were prepared at 1000×concentration in DMSO. The highest concentration was 30 mM. Serial 1:1dilutions were made from there for a 6- or 9-point curve (e.g., 20 mM,10 mM, 5 mM, etc). Compounds were then diluted 1:500 in media, and 100μL of the resulting solution was added to each well for a final dilutionof 1:1000. Each concentration of compound was tested in triplicate.Cells were incubated at 37° C. with 5% CO₂. After 72 hours, 20 μL ofCellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega) wasadded to each well. Cells were placed back in the incubator, and theabsorbance at 490 nm was read after 2-3 hours. The concentration ofcompound that decreased the number of metabolically active cells by 50%was determined and reported as the IC₅₀. “Percent Viability” wasdetermined by subtracting the average background value (media only) andexpressed as a ratio to the average value obtained from cells treatedwith only DMSO.

The compounds provided herein were tested in a panel of cell-basedassays of adherent cell types. The pharmacokinetics of the compoundsprovided herein were also profiled. The data is summarized in Table 1and Table 2.

TABLE 1 IC₅₀ in Triple Negative Breast Cancer Cell Lines (μM) CompoundNo. 1 2 3 Molecular Weight 496 510 529 MDA-MB-468 IC₅₀  5 μM 2 μM 4.5 μMMDA-MB-231 IC₅₀ 13 μM 6 μM   3 μM 4T1 IC₅₀ 15 μM 5 μM

TABLE 2 IC₅₀ in Adherent Cell Lines (μM) with Elevated eIF4E Cell LineIC₅₀: 1, 2, or 3 SK-MEL-2 (malignant melanoma) 2-16 μM SK-MEL-5(malignant melanoma)¹ 3-17 μM SK-MEL-28 (malignant melanoma)¹ 5-20 μMPanc-1 (ductal pancreatic cancer) 5-20 μM ¹B-RAF mutant

In one embodiment, the IC₅₀s of the compounds provided herein weredetermined in cell-based assays using suspension cells. In oneembodiment, the activity of the compounds provided herein weredetermined in a cell-based assay using B-cell acute lymphoblasticleukemia cell lines (Nalm-6, SupB-15, MHH-CALL-4), acute myelogenousleukemia cell lines (Kg1a), or multiple myeloma cell lines (NCI-H929 orU266). In one embodiment, the suspension cells used in the cell-basedassays may be a cell type selected from Table 3. Assays with suspensioncells were similar except that 40,000-60,000 cells were added to eachwell and compounds were added immediately after cell plating.

The compounds provided herein were tested in a panel of cell-basedassays of suspension cell types. The data is summarized in Table 3.

The IC₅₀s of the compounds provided herein and some reference compoundswere determined in cell-based assay using triple negative breast cancercell line MDA-MB-468. The results are summarized in Table 4.

TABLE 3 IC₅₀ of Compounds in Suspension Cell Types (μM) Cell Line IC₅₀:1, 2, or 3 Leukemia Nalm-6 (B-ALL)  5-8 μM SupB-15 (B-ALL) 11  14 μMMHH-CALL-4 (B-ALL)   16 μM KG1a (AML) 5-15 μM NCI-H929 (multiplemyeloma) 6-16 μM U266 (multliple myeloma) 11-20 μM 

TABLE 4 IC₅₀ of Compounds in MDA-MB-468 Cells MDA-MB- 468 CompoundNumber Structure IC₅₀ (μM) 1

5 2

2 3

4.5 4

12 5

5 6

7 7

2 8

1.5 9

5 10

3 Reference compound 1 

>20 Reference compound 2 

10 Reference compound 3 

>20 Reference compound 4 

17 Reference compound 5 

>20 Reference compound 6 

>20 Reference compound 7 

14 Reference compound 8 

>20 Reference compound 9 

>20 Reference compound 10

>20 Reference compound 11

>20 Reference compound 12

19 Reference compound 13

>20

C. Additional Assays

In one embodiment, the compounds provided herein were assayed fortranslation inhibition activity using an in vitro HeLa cell extracttranslation system with an m7GpppN-capped luciferase mRNA reporter. Inone embodiment, Compound 1 inhibited luciferase activity at 10 μM by97.4% vs. DMSO compared to 99.3% inhibition by cycloheximide. Withoutbeing limited to any particular theory, the inhibition of luciferaseactivity was specific to translation inhibition since the compoundshowed no inhibition of purified luciferase protein at 100 μM.

Cyclin D is one of the most commonly overexpressed genes in breastcancer and high levels correlate with poor prognosis. Furthermore,cyclin D overexpression is correlated with triple-negative basal-liketumors. In one embodiment, the effects of a compound provided herein oncyclin D overexpression were evaluated. MDA-MB-231 cells were treatedwith 2 μM and 10 μM of Compound 1 and 20 μM cycloheximide (CHX) for 12h. The density ratio of the cyclin D3 band to respective beta-actin bandwas determined by Western blot analysis and normalized to DMSO (100%).In one embodiment, 10 μM of Compound 1 showed a decrease in cyclin D3levels at 18 and 24 h.

Many proteins that drive cancer growth and survival (including thecyclins, c-myc, and Pim-1) have secondary structures in the 5′-UTR oftheir mRNA that limit the rate of translational initiation. In oneembodiment, the effects of a compound provided herein on translation ofsuch mRNAs relative to mRNAs without highly structured 5′-UTRs wereevaluated. In one embodiment, Compound 1 showed a preferentialinhibition of the highly structured 5′-UTR HB3 (triple stem loop)reporter.

In one embodiment, the compounds provided herein were assayed forinhibition of cancer associated fibroblasts in the tumor stroma. In oneprotocol, normal human lung fibroblasts (NHLFs) were serum starved for24 h then treated with or without TGF-β and 0.1% DMSO (control) or 10 μMor 20 μM Compound 1 or Compound 2 for 48 h. Cells were lysed andseparated by SDS-PAGE and blotted onto a PVDF membrane and incubatedeither with anti-α-SMA antibody or with anti-β-actin antibody (FIG. 1).

In another typical protocol: normal human lung fibroblasts (NHLFs) in6-well plates at ˜50% confluent were serum starved with DMEM (no FBS)for 24 h and treated with TGF-β [30 ng/ml] and the compounds providedherein [μM] for 48 h. Lysed with 200 μl MPER+HALT per well. 12-well SDSPAGE mini gels were loaded with similar amounts of total proteins asdetermined by Bradford (15-17 μl per lane). Semi dry transferred toPVDF, blocked for 1 h RT with TBST+1% BSA, 1:5000 mouse anti α-SMA O/N4C, and 1:5000 anti-mouse HRP 1 h RT. In TBST+1% BSA (FIG. 2).

D. Tumor Growth Inhibition in Mouse Xenograft Model for Breast Cancer

In one embodiment, the effects of a compound provided herein on tumorgrowth in a mouse animal model were evaluated. In specific embodiments,the mouse animal model was the MDA-MB-231 xenograft model for breastcancer. Studies were performed to evaluate the effect of a compoundprovided herein on the growth of MDA-MB-231 breast tumors in mice. Thetest system that was used is summarized below:

Species/strain: Mouse/nude Physiological state: ImmunocompromisedAge/weight range at Animals aged 5 to 6 weeks with body weight of startof study: approximately 20 g Animal supplier: Charles River LaboratoriesNumber/sex of 40/female animals: Identification: Prior to initiation ofdosing, animals were identified by ear punching. After randomization,all cages were labeled with protocol number, group, and animal numberswith appropriate color-coding Randomization: Animals were randomly andprospectively divided into treatment groups of animals each prior totumor induction. Cell Line: MDA-MB-231 breast cell carcinoma Cell LineSource: ATCC (HTB-26) Cell Culture Liebovitz's L-15, 10% FBS, 1%pen/strep Conditions: Tumor Cell Implant: 5.0 × 10⁶ cells,subcutaneously in 50% Matrigel

Animals were housed 10 mice per cage in micro-isolators, with sterilecorn cob bedding, food, and water. Mice were acclimated for 3 days andgiven food and tap water ad libitum. Animals were examined prior toinitiation of the study to assure adequate health and suitability.Animals that were found to be diseased or unsuitable were not assignedto the study. During the course of the study, 12-hour light/12-hour darkcycle were maintained. A nominal temperature range of 20-23° C. with arelative humidity between 30% and 70% was maintained. LabDiet5053-certified PicoLab Rodent Diet and sterile water were provided adlibitum during the study.

Exemplary Protocol: Ten mice per group were inoculated s.c. on the leftflank with 5×10⁶ MDA-MB-231 cells. When tumors reached a mean volume ofapproximately 100 mm³, animals began treatment with a compound providedherein (See Table 5). Test article or vehicle were given once daily byIP injection for up to 31 days. Tumors were evaluated every Monday,Wednesday and Friday, body weights and condition were evaluated on adaily basis.

Cell Culture: MDA-MB-231 breast cancer cells were grown in Liebowitz'sL-15 with 10% fetal bovine serum and 1% pen/strep. Cells were routinelytrypsinized and passaged 1:3. On the day of implantation, cells werewashed in PBS, trypsinized and resuspended in complete media. Cells werewashed 3× in serum free media (centrifuged 1000 rpm for 5 min). Cellswere resuspended to a density of 1×10⁸ cells/mL and diluted 1:1 withMatrigel. Cells were implanted s.c. using a 23G needle in a volume of0.1 mL.

TABLE 5 Study Groups Treated With Compound Number of Test Group animalsInoculum article Dose Schedule* 1 10♀  MDA-MB- Vehicle NA Once Daily,231, 5 × 10⁶ Days 1 to 31 cells 2 8♀ MDA-MB- Com- 50/25 mg/kg OnceDaily, 231, 5 × 10⁶ pound 1 Days 1 to 31 cells 3 8♀ MDA-MB- Paclitaxel   6 mg/kg Once Daily, 231, 5 × 10⁶ Days 1, 3, 5 cells *Therapycommenced when tumors reach approximately 100 mm³; dosing schedule anddosing amount may be adjusted (e.g., after the initiation of compoundtreatment) depending on individual compound/experiment.

Tumor Measurement: Tumors were monitored daily. If, during a dailyevaluation, an animal's tumor appeared to have exceeded 1500 mm³, thetumor was measured; and animals with tumors greater than 1500 mm³ and/orthat had become necrotic and/or hindered movement were euthanized.Tumors were measured twice weekly by measuring each tumor in 2dimensions, along the largest dimension (length, L) and perpendicular tothis dimension (width, W). Tumor weights were calculated using thestandard formula: (L×W²)/2. The mean tumor weight and standard error ofthe mean were calculated for each group at each time point. An ANOVA wasused to compare differences of primary tumor volume.

Animal Weight: All animals were weighed twice weekly throughout thestudy. Group weight change was expressed as a daily group mean weight.Animals that lost greater than 20% of their total starting body weightwere euthanized.

In one embodiment, Compound 1 was dosed in mice at a dose of, forexample, qd 50 mg/kg, and the dose was reduced to 25 mg/kg on day 7. Inone embodiment, mean tumor volume at Day 31 for the vehicle group was898±260 mm³, while mean tumor volume at Day 31 for the group of micetreated with Compound 1 was 276±119 mm³. In one embodiment, mean weightgain for the vehicle group was 4.2%, while mean weight gain for thegroup of mice treated with Compound 1 was 0.1%.

On day 32, the group of mice treated with Compound 1 was subdivided into2 groups. For the next 10 days, one group continued to receive treatmentwhile the other did not. In one embodiment, tumor growth did not resumewithin 10 days of the withdrawal of Compound 1.

At study termination, mice still undergoing treatment were given a finaldose of compound and sacrificed 2 h later. Average concentrations ofcompounds in plasma and tumor were determined. In one embodiment,detectable levels of Compound 1 were found in both plasma and tumorsamples from the mice that discontinued treatment on Day 31, indicatingthat less frequent dosing of Compound 1 will likely be an option.

In one embodiment, a triple negative breast cancer xenograft(MDA-MB-231) was performed on Compound 1 and Compound 2 dosed IP and PO.Mean tumor volumes over time were calculated from length and widthmeasurements. Treatment was initiated when average tumor size reached100 mm³. Compound 1 and Compound 2 were dosed at 50 mg/kg IP and 100mg/kg PO. Doses were either skipped or cut in half for those mice thatlost >15% of their body weight. The tumor growth inhibition data issummarized in FIGS. 3-6 and Table 6.

TABLE 6 Plasma and Tumor Concentrations of Lead Compounds at SacrificeAve. Tumor Ave. Conc. (μM/g Compound Treated until No. of Day Plasma oftumor No. the end? Animals Treatment Dose Sacrificed Conc. (μM) tissue)1 Yes 3 50/25 mg/kg 45 2.33 ± 0.27 1.25 ± 0.09 1 No 4 None after day 3145 0.05 ± 0.02 0.07 ± 0.04

TABLE 7 Comprehensive PK studies and Oral Bioavailability of Compounds 1and 2 IV IV Admin- Admin- PO PO istration istration AdministrationAdministration (5 mg/kg) (5 mg/kg) (25 mg/kg) (25 mg/kg) Compound C0(ng/mL) T1/2 (h) C0 (ng/mL) T1/2 (h) Compound 1 54,647 2.1 5150 1.5Mouse Compound 2 53,652 2.9 3613 2.4 Mouse Compound 2 68,933 1.6 27,600ND (>>6) Rat Animals were dosed at 5 mg/kg IV and 25 mg/kg PO. Plasmasamples were collected at times ranging from 0 to 6 h and analyzed byLC-MS/MS.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference intheir entireties.

What is claimed:
 1. A compound of formula (I):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X is NH, and Y is S(O)₂; or X is S(O)₂, and Y is NH; R′ is hydrogen, halogen, cyano, OH, OC(O)R_(a), C(O)R_(a), C(O)OR_(a), C(O)NR_(a)R_(b), NR_(a)C(O)R_(b), NR_(a)R_(b), OS(O)R_(a), SR_(a), S(O)R_(a), S(O)₂R_(a), S(O)₂NR_(a)R_(b), NR_(a)S(O)₂R_(b), (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are each optionally substituted with one or more halogen; n is 2, 3, or 4; each occurrence of R is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionally substituted with one or more halogen; and R_(a) and R_(b) are each independently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, (C₇-C₁₂)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R_(a) and R_(b) together form a 3 to 10 membered ring.
 2. The compound of claim 1, having formula (II):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: R₁ is independently (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionally substituted with one or more halogen; R₂ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionally substituted with one or more halogen; and R₃ is independently (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl, each of which is optionally substituted with one or more halogen.
 3. The compound of claim 2, having formula (II-A):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 4. The compound of claim 3, having formula (II-A-1):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 5. The compound of any one of claims 1-4, wherein X is NH, and Y is S(O)₂.
 6. The compound of any one of claims 1-4, wherein X is S(O)₂, and Y is NH.
 7. The compound of claim 4, having formula (III-A-1):

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 8. The compound of any one of claims 1-7, wherein R′ is hydrogen, halogen, (C₁-C₄)alkyl, or (C₁-C₄)alkoxy, wherein the alkyl and alkoxyl are each optionally substituted with one or more halogen.
 9. The compound of claim 8, wherein R′ is hydrogen, halogen, or (C₁-C₄)alkyl optionally substituted with one or more halogen.
 10. The compound of any one of claims 1-8, wherein R′ is hydrogen, F, Cl, Br, (C₁-C₄)alkyl, CF₃, or OCF₃.
 11. The compound of any one of claims 1-10, wherein R′ is hydrogen, Cl, Br, or (C₁-C₄)alkyl.
 12. The compound of any one of claims 1-11, wherein R′ is hydrogen, chloro, bromo, or methyl.
 13. The compound of any one of claims 1-12, wherein R′ is hydrogen.
 14. The compound of any one of claims 1-12, wherein R′ is methyl.
 15. The compound of any one of claims 1-12, wherein R′ is chloro.
 16. The compound of any one of claims 1-12, wherein R′ is bromo.
 17. The compound of any one of claims 2-16, wherein R₁, R₂, and R₃ are independently (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl.
 18. The compound of any one of claims 2-17, wherein R₁ is (C₁-C₄)alkyl.
 19. The compound of any one of claims 2-18, wherein R₁ is methyl, ethyl, or isopropyl.
 20. The compound of any one of claims 2-19, wherein R₂ is hydrogen, or (C₁-C₄)alkyl.
 21. The compound of any one of claims 2-20, wherein R₂ is methyl, isopropyl, or tert-butyl.
 22. The compound of any one of claims 2-21, wherein R₃ is (C₁-C₄)alkyl.
 23. The compound of any one of claims 2-22, wherein R₃ is methyl, ethyl, or isopropyl.
 24. The compound of claim 6, wherein the compound is:


25. The compound of claim 4, wherein X is S(O)₂, Y is NH, R′ is hydrogen, and R₁, R₂, and R₃ are isopropyl.
 26. A pharmaceutical composition comprising a compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.
 27. The pharmaceutical composition of claim 25, further comprising one or more additional active agents.
 28. The pharmaceutical composition of claim 27, further comprising paclitaxel or docetaxel.
 29. The pharmaceutical composition of claim 26, wherein the composition is formulated for single dose administration.
 30. The pharmaceutical composition of claim 26, wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
 31. The pharmaceutical composition of claim 29, wherein the oral dosage form is a tablet or capsule.
 32. A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by protein translation initiation, comprising administering a compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 26 or
 27. 33. A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by eIF4E, comprising administering a compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 26 or
 27. 34. The method of any one of claims 32-33, wherein the disorder is cancer, metastatic cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+breast cancer, ER− breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors.
 35. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, comprising administering a compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 26 or 27, wherein the disorder is cancer, metastatic breast cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+breast cancer, ER− breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors.
 36. The method of any one of claim 34 or 35, wherein the cancer is resistant to conventional therapy.
 37. The method of any one of claim 34 or 35, wherein the cancer is vincristine-resistant.
 38. The method of any one of claim 34 or 35, wherein the cancer is taxol-resistant.
 39. The method of any one of claim 34 or 35, wherein the cancer is cytarabine-resistant.
 40. The method of any one of claim 34 or 35, wherein the cancer is doxorubicin-resistant.
 41. A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by protein translation initiation, comprising administering a compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 26 or 27, together with one or more additional active agents.
 42. The method of claim 41, wherein the additional active agents comprises paclitaxel or docetaxel.
 43. A method of preventing metastasis comprising administering a compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 26 or
 27. 44. A method of treating, preventing, or ameliorating fibrosis, comprising contacting a human fibroblast with a compound of any one of claims 1-25, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 26 or
 27. 